AU642178B2 - New tricyclic compounds - Google Patents

Abstract

The present invention is directed to new pharmaceutically active compounds with 5-HT3 receptor antagonist activity of Formula I: <CHEM> in which the dashed line denotes an optional double bond; n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2; each R<1> is halogen, hydroxy, alkoxy (optionally substituted with phenyl), alkyl, nitro, amino, amino carbonyl, (alkyl)amino, di(alkyl)amino, and (alkanoyl)amino; each R<2> is alkyl; and R<3> is <CHEM> in which u, x, y, and z are all independently an integer from 1 to 3; and R<4> and R<5> are independently alkyl, cycloalkyl, cycloalkylalkyl, or a group (CH2)tR6 where t is 1 or 2 and R6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from alkyl, alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and alkyl (optionally substituted).

Description

642178 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Form Class Int. Class Application Number: Lodged: c omplete Specification Lodged: Accepted: Published: Priority: Related Art 4a S tiame of Applicant: SYNTEX INC.

S 0 Address of Applicant:

IL

Actual Inventor: Address for Service 3401 Hillview Avenue, States of America Palo Alto, California 94304, United JACOB BERGER, ROBIN D. CLARK, RICHARD M. EGLEN, WILLIAM L. SMITH and KLAUS K. WEINHARDT WATERMARK PATENT TRADEMARK ATTORNEYS.

LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: NEW TRICYCLIC COMPOUNDS The following statement is a full description of this invention, including the best method of performing it known to us -1- NEW TRICYCLIC COMPOUNDS BACKGROUND OF THE INVENTION Field of the Invention 10 This invention relates to novel pharmaceutical tricyclic compounds, pharmaceutical compositions containing them and methods for their use and methods for preparing these compounds. In particular, it relates to tricyclic 5-HT 3 receptor antagonists 15 containing a bridged bicyclic amine substituent. The invention also relates to novel intermediates for making the new tricycli.c compounds.

Background of The Invention 20 Compounds with highly selective actions on (serotonin or 5-hydroxytryptamine) receptor subtypes show clear potential for therapeutic benefit and provide tools with which scientists can better understand the role of 5-HT in disease. A number of different 25 receptor subtypes have been identified. Some of these are designated as 5-HT 1 5-HT 2 and 5-HT 3 receptors.

Certain compounds having 5-HT 3 receptor mediating activity are useful for treating emesis, CNS disorders, cognitive performance disorders, drug dependency disorders, pain migraine), cardiovascular disorders and gastrointestinal disorders. See, for example, an article entitled "Drugs Acting On Receptors" appearing in The Lancet September 23, 1989.

26890-FF -2- Novel tricyclic compounds have now been discovered that are useful inter alia for treating a variety of conditions influenced by the 5-HT 3 receptor. The compounds of this invention are active at very low levels, particularly in the treatment of emesis but show also activitv in the treatment of other disorders as shown below.

o soe 0 0035

I.OHVM

26890-FF -3- SUMMARY OF THE INVENTION In a first aspect, this invention provides a compound of Formula I: 0 VCC H2

R')

in which the dashed line denotes an optional double bond; 15 n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2; each R 1 is independently selected from halogen, lose hydroxy, lower Fxlkoxy (optionally substituted 20 with phenyl), lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; each R 2 is lower alkyl; and

R

3 is selected from 1HVM26890-FF -4- 2 )NR Ca)

N

b)

(C)

0*10 CC~a) (d) .0% Soso* in which 15u, x, y and z are each independently an integer from 1 to 3; and

R

4 and R5are independently C 1 7 alkyl, C 3 8 cycloalkyl, C 3 8 cycloalkyl-C..

2 alkyl, or a group 4 (CH 2 )tR 6 where t is 1 or 2 and R 6 is thienyl, 00:4 20 pyrrolyl or furyl optionally further substituted by one or two substituents selected from Cl..

6 alkyl, Osseo:Cl-.

6 alkoxy, trifluoiomethyl or halogen, or is *Goes:phenyl optionally substituted by one or two substituents selected from C 1 4 alkoxy, 25*0 trifluoromethyl, halogen, nitro, carboxy, .66. esterified carboxy, and C 1 4 alkyl (optionally 4. S substituted by hydroxy, C 1 4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy); or a pharmaceutically acceptable salt thereof or N-oxide derivative thereof, or an individual isomer or mixture of isomers thereof.

l0HVM ~1VM26890-FF In a second aspect, this invention provides a pharmaceutical composition which contains a compound of Formula I, preferably in admixture with one or more suitable excipients.

In a third aspect, this invention provides a method of treating emesis, gastrointestinal disorders, CNS disorders including cognitive performance disorders and drug dependency, cardiovascular disorders or pain by administering a therapeutically effective amount of a compound of Formula I to a subject afflicted with such a 0condition.

S* In a fourth aspect, this invention provides compounds of Formula II which are useful intermediates for preparing compounds of Formula I: 0 /3 (66 NH (RZ(c wherein n, p, q, R 1

R

2 and R 3 are as defined for Formula I.

6 A fifth aspect of this invention is a process for 0 preparing compounds of Formula I and is set forth in the "Detailed Description Of The Invention." 26890-FF -6- DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: "Alkyl" means a straight or branched saturated hydrocarbon radical having from one to the number of carbon atoms designated. For example C 1 7 alkyl is alkyl having at least one but no more than seven carbon atoms, e.g. methyl, ethyl, i-propyl, n-propyl, n-butyl, S. pentyl, heptyl and the like.

"Lower alkyl" means an alkyl of one to six carbon atoms.

"Lower alkoxy", "(lower alkyl)amino", "di(lower alkyl)amino", "(lower alkanoyl)amino", and similar terms mean alkoxy, alkylamino, dialkylamino, alkanoylamino, etc. in which the or each alkyl radical is a "lower alkyl" as described above.

20 "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred halogens are chlorine and bromine; "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

"Pharmaceutically acceptal"e salts" means salts which possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, 26890-FF .I I r -7cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic) acid, *06* :3-phenyipropionic acid, trimethyl-acetic acid, tertiary S* butylacetic acid, lauryl sulfuric acid, gluconic acid, *6* 4000 glutamic acid, hydroynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.

The compounds of Formula I with a R 1 hydroxy group @000 20 are capable of forming salts with inorganic or organic bases. Preferred pharmaceutically acceptable bases 0 include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, calcium hydroxide and 00.. organic bases such as diethanolamine, tromethamine, 25 N-methylglucamine, ethanolamine, triethanolamine and others.

4" "N-oxide derivative" of a compound means the form 00 of a compound of Formula I wherein the nitrogen of the

R

3 moiety of Formula I is in the oxidized state, e.g.

26890-FF 1 -8- In defining the subject matter of this invention reference is made in the structure to substituents (Rl) and (R 2 It should be noted that the list of substituents of R 1 and R 2 does not include hydrogen, and each of p and q can be 0. It is to be understood that when p or q is 0, the respective ring structures will not be substituted and thus will have only hydrogens around the ring.

"Animal" includes humans, non-human mammals (such 1 as dogs, cats, rabbits, cattle, horses, sheep, goats, swine, and deer) and non-mammals such as birds and the like.

"Disease" specifically includes any unhealthy condition of an animal or part thereof and may be caused 8 by, or incident to, medical or veterinary therapy re 15 ri* applied to that animal, i.e. the "side effects" of such therapy. Thus, "disease" here includes the nausea and emesis caused by therapy with agents having emetogenic side effects, in particular by therapy for cancer, such 20 as chemotherapy with cytotoxic agents and radiotherapy.

"Treatment" means any treatment of a disease in an animal and includes: preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet 25 experience or display symptoms of the disease, inhibiting the disease, i.e. arresting its development, or relieving the disease, i.e causing regression of the disease.

"Effective amount" for a disease means that amount which, when administered to an animal in need thereof, is sufficient to effect treatment, as defined above, for that disease.

26890-FF -9- Certain compounds of F- .ula I and Formula II may exist as optical isomers. In the compounds of the invention, any isomer or mixture of isomers may be used and the claims are intended to cover the individual isomer and mixtures thereof, unless otherwise restricted. The invention includes all optical isomers of any asymmetrical compound of Formula I, as well as mixtures thereof.

"Isomerism" refers to compounds having the same 1 atomic mass and atomic number but differing in one or more physical or chemical properties. Various types of isomers include the following: "Stereoisomer" refers to a chemical compound having 9 the same molecular weight, chemical composition, and a.

1 constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light. However, some pure 20 stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation.

"Optical isomer" describes one type of stereo isomerism which manifests itself by the rotation that the isomer, either pure or in solution, imparts to the plane of polarized light. It is caused in many instances by the attachment of four different chemical atoms or groups to at least one of the carbon atoms in a molecule.

Stereoisomers or optical isomers that are mirror images of one another are termed "enantiomers" and may be said to be enanticmeric. Chiral groups that are mirror images of one another are termed enantiomeric groups.

26890-FF V I e Enantiomers whose absolute configurations are not known may be differentijted as dextrorotatory (prefix or laevorotatory (prefix depending on the direction in which, under specified experimental conditions, they rotate the plane of polarized light.

When equal amounts of enantiomeric molecules are present together, the product is termed racemic, independently of whether it is crystalline, liquid, or gaseous. A homogeneous solid phase composed of 1 equimolar amounts of enantiomeric molecules is termed a 00 •racemic compound. A mixture of equimolar amounts of enantiomeric molecules present as separate solid phases is termed a racemic mixture. Any homogeneous phase containing equimolar amounts of enantiomeric molecules is termed a racemate.

"Diastereoisomer" refers to stereoisomers some or all of which are dissymmetric but which are not mirror images of each other. Diastereoisomers corresponding to a given structural formula must have at least two *O 20 asymmetric atons. A compound having two asymmetric atoms will usually exist in four diastereoisomeric forms, i.e. (-)-erythro, (+)-erythro, (-)-threo and (+)-threo.

The optically active compounds herein can be designated by a number of conventions; the R- and S-sequencing rules of Cahn and Prelog; erythro and threo isomers; D- and L-isomer;; d- and 1-isomers; and and isomers, which indicates the direction a plane of polarized light is rotated by the chemical structure, either pure or in solution. These conventions are well known in the art and are described in detail by E.L. Eliel in Stereochemistry of Carbon Compounds, published by McGraw Hill Book Company, Inc.

of New York in 1962 and trferences cited therein, Thus, 26890-FF -11these isomers may be described as or a d,l-pair; or or a D,L-pair; or or an R,S-pair; depending upon the nomenclature system employed. In general, this application will use the and (RS) designation.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in 1 which it does not. For example, "optionally substituted phenyl" means that the phenyl may or may not be substituted and that the description includes both unsubstituted phenyl and phenyl wherein there is substitution; "optionally followed by converting the 15 free base to the acid addition salt" means that said conversion may or may not be carried out in order for the process described to fall within the invention, and the invention includes those processes wherein the free base is converted to the acid addition salt and those processes in which it is not.

20 Certain R 3 substituents are of particular interest for the compounds of this invention and are therefore defined specifically. In some cases the R 3 substituent will exhibit a chiral center at the ring carbon which is bonded to the amide nitrogen. It is to be understood that a straight line representing the covalent bond between the chiral carbon and the amide nitrogen is 40 understood to represent either the R or S configuration, or a mixture (not necessarily racemic) thereof. These

R

3 substituents of particular interest are as follows: subformula where y is 2 having the specific formula 26890-FF -12- N'1 4 0 gee* *49 8 4 so 4 604 is referred to as l-azabicyclo[2.2.2]oct-3-yl; subforrnula where y is 2 having the specific formula

NN

is referred to as 1-azabicyclo[2.2.2]oct-4-yl; subformula where x is 3 and R4 is methyl having the specific formula

-OCH

3 is referred to as erdo-9-methyl-g--azabicyclo llnon-3-yl; 1 HVM26890-FF I 9 -13subformula where x is 2 and R 4 is methyl having the specific formula

N-CH

3

H

is referred to as endo-8-Inethyl-8-azabicyclIo[3.2.lloct-3-yl; *k Ca subformula where x is 2 and R 4 is methyl having the specific formula

H

is referred to as exo-8-methyl-8-azabicyclo[3.2.]oct-3-yl; and *see#; *:seek(6) subformula wherein u is 2 having the specific formula

CI

1 HVM2689 0-FF -14is referred to as endo-J,--azabicyclo[3.3.llnon--4-yl.

The compounds of Formula I are named in accordance with generally acceptable nomenclature rules established by "Chemical Abstracts." The naming depends primarily on whether n is 1, 2 or 3. For example, the compound of the following formula where n 1 and

R

3 1-azabicyclo-112.2.2]oct-4-yl: S a a 6* a S 9* S9 a a a a a.

a a 5 4 is nav~ed 2-(1-azabicycloll2.2.2]oct-4-yl)- 1, 2,4, 5-tetrahydrocyclopent Ldel isoquinolin- 1-one.

The compound of the following formula where n =2 and R 3 1-azabicyclo[2.2.2]oct-4-yl: a 9.

9* a aa S.

a

S

see, as a 0

S

a..

a. 'a aa is named 2-(l-azabicycloi2.2.2]oct-4-yl)- 4, 5, 6-tetrahydro-1H-benz (del isoquinolin-l-ofle.

The compound of the following formula where n 3 and R 3 =1-azabicyclo[2.2.2]oct-4-yl: 280F 26890-FF 9 0 N 0 8 3 7a 3a 7 4 6 is named 2-(azabiyclo[2.2.2]oct-4-yl)- 1,2,4,5,6,7-hexahydrocyclohept[delisoquinolin-l-one.

Utility The compounds of this invention, as defined by Formula I, exhibit pharmaceutical activity and in S00: 15 particular 5-HT 3 receptor antagonist activity. As such, these compounds are useful for treating a broad range of conditions in animals, particularly humans, in which the 5-HT 3 receptor plays a role. Examples of conditions that may be treated using the compounds of this invention include emesis, gastrointestinal disorders, central nervous system (CNS) disorders including cognitive e00 •performance disorders, drug dependency, etc., cardiovascular disorders and pain.

For purposes of this patent application, 25 particularly the claims the term "emesis" will have a meaning that is broader than the normal, dictionary 0 definition and includes not only vomiting, but also nausea and retching. Such a condition of emesis may be induced by or result from the administration of chemotherapeutic or cytotoxic agents or radiation \n cancer treatment or from the exposure to radiation, surgical operations or anesthesia or motion sickness (caused by riding in a vehicle, airplane, vessel, etc.).

26890-FF -16- The compounds of this invention can be referred to as anti-emetics and are particularly valuable for treating (especially preventing) emesis induced in cancer patients by treatments with cytotoxic pharmaceutical agents or radiation. Such cytotoxic agents include platinum anti-cancer agents such as cisplatin (cis-diamminedichloroplatinum), as well as non-platinum anti-cancer drugs such as cyclophosphamide (cytoxin), vincristrine (leurocristine), procarbazine (N-(l-methylethyl)-4-[(2-methylhyhydrazino)methyl]benzamide), methotrexate, fluorouracil, mechlorethamine hydrochloride (2-chloro-N-(2-chloroethyl)-N-methyl- O ,b ethanamine hydrochloride), doxorubicin, adriamycin, dactinomycin (actinomycin-D) cytarabine, carmustine, dacarbazine, and others listed at page 1143 of the Journal of Clinical Oncology 1989; 1143.

The compounds of the invention may also be useful for treating post-operative nausea and vomiting and motion sickness and for the treatment of all conditions 2 described hereinbefore.

The compounds of Formula I are useful in the treatment of gastrointestinal disorde.s of the stomach, esophagus and both the large and small intestines). Examples of specific conditions that may be 25 treated using the compounds of this invention include, but are not limited to, dyspepsia (including non-ulcer S* dyspepsia), gastric stasis, peptic ulcer, reflux esophagitis, flatulence, bile reflux gastritis, pseudo-obstruction syndrome, irritable colon syndrome 30 (which may result in chronic constipation or diarrhea), diverticular disease, biliary dysmotility (which may result in sphincter of Oddi dysfunction and "sludge" or microscopic crystals in the gall bladder), gastroparesis diabetic, postsurgical or idiopathic), irritable 26890-FF I I I -17bowel syndrome and retarded gastric emptying. The compounds of the invention are also useful as short-term prokinetics to facilitate diagnostic radiology and intestinal intubation. In addition the compounds are useful for treating diarrhea, particularly diarrhea induced by cholera and carcinoid syndrome.

The compounds of Formula I are useful in treating CNS disorders. Some of the categories of treatable CNS disorders include cognitive disorders, psychoses, 1 anxiety/depression and obsessive/compulsive behavior.

Cognitive disorders include attentional or memory deficit, dementia states (including senile dementia of the Alzheimer's type and aging), cerebral vascular deficiency and Parkinson's disease. Psychoses that may 1 be treated using the compounds of this invention include paranoia and schizophrenia. Representative, treatable anxiety/depressive states include anticipatory anxiety prior to surgery, dental work, etc.), depression, f mania, convulsions and anxiety caused by withdrawal from addictive substances such as nicotine, alcohol, common narcotics, cocaine and other drugs of abuse. Finally obsessive/compulsive behavior, e.g. that which results in obesity, may be treated using the compounds of this 9 invention.

5 Cardiovascular disorders that may be treated using 25 a compound of this invention are those that are mediated by the presence of serotonin. Examples of such disorders include arrhythmias and hypertension.

0 It is thought that the compounds of this invention 30 prevent certain adverse nervous transmissions and/or prevent vasodilation and thus reduce the perceived level of pain. Examples of pain treatable using a compound of this invention include cluster headaches, migraines, 26890-FF -18trigeminal neuralgia and visceral pain that caused by abnormal distension of hollow visceral organs).

To determine the 5-HT 3 antagonist activity of compounds of this invention one of ordinary skill may use the Rat Cerebral Cortex Binding Assay, a predictive in vitro assay which assesses the binding affinity of a compound for the 5-HT 3 receptor. The method is described in Kilpatrick, Jones, B.J. and Tyers, M.B., Nature 1987; 330: 24-31. The assay as adapted for 1 testing compounds of the invention and results are set out in Example 11 of this application. The compounds of Formula I exhibit affinity for the 5-HT 3 receptor in this assay.

The von Bezold-Jarisch test for 5-HT 3 antagonist activity in rats is an accepted test for determining 15 5-HT 3 antagonist activity in vivo by measuring the von Bezold-Jarisch reflex in anesthetized rats. See, e.g., Butler, Hill, Ireland, Jordan, C.C., Tylers, Brit. J. Pharmacol. 1988; 94: 397-412; 2 Cohen, Bloomquist, Gidda, Lacefield, W., J. Pharmacol. Exp. Ther. 1989; 248: 197-201; and Fozard, MDL 72222: Arch. Pharmacol. 1984; 326: 36-44. The compounds of the invention exhibit activity in the von Bezold-Jarisch test. The details of the 25 procedure (as modified for testing the compounds of the invention) and results are set out in Example 14 of this application. Compounds of Formula I reduce cisplatin-induced emesis in the ferret.

The cisplatin-induced emesis test in ferrets is an 30 accepted test for determining anti-emetic activity in vivo, see e.g. Costall, Domeney, A.M., Naylor, and Tattersall, Neuropharmacology 1986; 25(8): 959-961; and Miner, W.D. and Sanger G.J., Brit. J. Pharmacol. 1986; 88: 497-499. A general 26890-FF 9 9 I -19description and results are set out in Example 13 of this application. Compounds of Formula I reduce cisplatin-induced emesis in the ferret.

Anti-emetic properties in the control of emesis in dogs due to administration of platinum anti-cancer drugs are also determined by a modification of the method described by Smith, Alphin, Jackson, C.B., and Sancilio, J. Pharm. Pharmacol. 1989; 41: 101-105; and Gylys, Res. Commun. Chem. Pathol.

Pharmacol. 1979; 23(1): 61-68 as follows: cisplatin (cis-diamminedichloroplatinum) is administered at a dose of 3 mg/kg intravenously to non-fasted dogs (both sexes). Sixty minutes after cisplatin administration, S* the test drug in saline at a dose volume of 0.1 ml/kg is 15 administered intravenously. A control group of dogs is given the cisplatin followed by saline at 60 min, without test drug. The dogs are observed continuously for a period of 5 hr counting the number of emetic episodes and comparing them to emetic episodes observed for the 2 controls.

The utility for treating gastrointestinal disorders is determined by assaying the gastrokinetic 0 pharmacological activity using the method of Droppleman, Gregory, and Alphin, R.S., SJ. Pharmacol. Methods 1980; 227-30 wherein the rate 25 Sof emptying of a test meal in rats compared to controls Sa was observed. The Droppleman et al. method is an accepted method for determining gastrointestinal activity in vivo. The compounds of the invention exhibit activity **in the Droppleman et al. method, the detail of which is set out in Example 12. The compounds of Formula I show activity in this assay.

The utility for treatment of a CNS disorder such as anxiety (anxiolytic activity) is determined by the 26890-FF art-recognized Crawley and Goodwin two-compartment exploratory model as described in Kilfoil, T., Michel, Montgomery, and Whiting, R.L., Neuropharmacology 1989;-28(9): 901-905. In brief, the method involves determining whether a compound reduces the natural anxiety of mice in brightly-lit areas.

Compounds of the invention are active in this art recognized test. An example is set forth in Example of this application. Compounds of Formula I are aictive 1 in this test.

Cognition enhancing activity may be determined by the mouse habituation/cognitive enhancement test. See procedures described in Barnes, Costall, Kelly, Naylor, Onaivi, Tomkins, D.M. and 15 Tyers, M.B. Br. J. Pharmacol. 98, 693P (1989). This procedure utilizes the exploratory model described above to test for improvements in the impaired cognitive performance of aged mice. A detailed description is set forth in Example 18 of this application. Compounds of 2 Formula I enhance cognitive performance in this test.

Anxiolytic activity during withdrawal from drugs of abuse is determined by the mouse light/dark withdrawal anxiety test. This procedure utilizes the exploratory model described above to test for anxiolytic activity 25 after administration and subsequent abrupt cessation of 25 alcohol, cocaine or nicotine treatments. A detailed description is set for in Example 17 of this application. Compounds of Formula I are effective at reversing the drug withdrawal-induced anxiety in this test.

All of the aforementioned citations to in vitro and in vivo methods for determining activity of the compounds of this invention and other documents cited herein are incorporated herein by reference.

26890-FF

I

-21- In summary then another aspect of this invention is a method for treating an animal exhibiting a condition in which the 5-HT 3 receptor plays a role, e.g. where the condition is chosen from emesis, a gastrointestinal a CNS disorder, a cardiovascular disorder and pain, which method comprises administering a therapeutically effective amount of a compound of Formula I to such mammal. The compounds are particularly valuable for treating humans.

A therapeutically effective amount of a compound is an amount that is efficacious in treating the condition, i.e. the disease. The exact amount administered may vary over a wide range depending on the degree of severity of the specific condition being treated, age of the subject, 15 relative health of the subject and other factors. A therapeutically effective amount may vary from about 0.000001 mg (1 nanogram per Kg body weight per day to about 10.0 mg/Kg body weight per day. Preferably the amount will be about 10 ng/Kg/day to about 1.0 mg/Kg/day, especially for anti-emetic purposes. Thus, for a 70 Kg human, a therapeutically effective amount may be from about 70 ng/day to 700 mg/day, preferably about 700 ng/day to about 70 mg/day.

25 Adminsiqration and Pharmaceutical Composition S* The compounds of this invention may be.administered via any of the usual and acceptable modes known in the art, either singly or in combination with another compound of this invention or with another therapeutic 30 agent. Generally a compound of this invention is administered as a pharmaceutical composition with a pharmaceutically acceptable excipient and is administered orally, systemically transdermally, intranasally or by suppository) or parenterally intramuscularly 26890-FF I -22intravenously [iv] or subcutaneously The compounds of the invention can thus be administered in a composition that is a semisolid, powder, aerosol, solution, suspension or other appropriate composition, as discussed hereinafter.

A pharmaceutical composition comprises a compound of Formula I, wherein each substituent is defi&ed hereinabove, preferably in combination with a pharmaceutically acceptable excipient. Such excipient is one that is non-toxic and acts to aid in the administration of the compound of this invention. Such excipient may be any solid, liquid, semisolid, gaseous (in case of an aerosol) excipient that is generally 6* available to one of skill in the art and that does not adversely affect the activity of the active agent.

In general, the pharmaceutical composition of this 0 invention will contain a therapeutically effective amount z of a compound in combination with at least one excipient. Depending on the type of formulation, size of 2 a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences the amount of compound of this invention may vary over a wide range in the composition. In general, the final composition will comprise about 0.001%w to about 99.5%w of a compound of the invention with the remainder being the excipient or excipients. Preferably the level of active compound will be about 0.01%w to about 10.0% and most preferably about 0.1%w to about 1.0%w, with the remainder being a suitable excipient or excipients.

30 Useful pharmaceutical excipients for the preparation of the pharmaceutical compositions hereof can be solids, semisolids, liquids or gases. Thus, the compositions can take the form of tablets, pills, 26890-FF -23capsules, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. Solid pharmaceutical eycipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, ind the like. Liquid and Pemisolid exciiients may be selected from water, et.ianol, glyce-ol, propylene glycol, various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions.

Compressed gases are frequently used to dispense the active ingredient in aerosol form. Inert gases suitable for this purpose are nitroqen, carbon dioxide, nitrous se" oxide, etc. Other suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

Prefer bly the pharmaceutical composition is auministered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.

oo* Preenty Preferred Embodiments While the broadest definitition of this invention is set forth in the Summary of the Invention as a compound of Formula I wherein each of n, p, q, R 1

R

2

R

3

R

4

R

5 u, x, y and z is defined in its broadest 30 aspect, certain compounds of the invention are preferred. For example, the compounds of Formula I wherein p is 0, 1, or 2; n is 1 or 2; q is 0, R 1 is halogen, lower alkoxy or amino; and if R 3 comprises R 4 and R 5 they are each lower alkyl or R 3 is a bicyclic 26890-FF -24substituent as specified in the Summary of the Invention without further substituents. Of this subgroup those of particular interest include compounds of Formula I wherein p is 0, the dashed line represents a double bond and if R 3 comprises R 4 and R 5 they are each methyl, with particularly preferred compounds being those wherein

R

3 is l-azabicyclo[2.2.2]oct-3-yl; 1-azabicyclo-[22.2.2]oct-4-yl; endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl; endo-8-methyl-8-azabicyclo[3.2.1].ct-3-yl; exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl; or endo-1-azabicyclo[3.3.1]non-4-yl. Representative examples are set out in Examples 4 and Another subgroup of particular interest includes 15 compounds of Formula I wherein n is 1 or 2; p and q are both 0; the dashed line represents 2 hydrugens; and if

R

3 comprises R 4 and R 5 they are each methyl or R 3 is a bicyclic substituent as specified above without further substituents. Particularly preferred compounds are 2 those wherein R 3 is l-azabicyclo[2.2.2]oct-3-yl; 1-azabicyclo-[2.2.2]oct-4-yl; too* endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl; endo-8-methyl-8-azabicyclo[3.2.1 ]oct-3-yl; exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl; or endo-l-azabicyclo[33.3.1]non-4-yl. Representative compounds are made by following the procedure set forth in Example 7.

S Still another subgroup of compounds of particular interest include those of Formula I wherein p is 0, 1 or 2 i(especially where p is n is 3; q is 0; R is halogen, lower alkoxy or amino; and if R 3 comprises R 4 and R 5 1hey are each lower alkyl (particularly methyl) or R 3 is a bicyclic substituent as specified above without further substituents. Of these, compounds where the dashed line is a double bond are of particular 26890-FF 3 interest, particularly those wherein

R

3 is l-azabicyclo[2.2.2]oct-3-yl; 1-azabicyclo-[2.2.2]oct-4-yl; endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl; endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl; exo-8-methyl- 8-azabicyclo[3.2.1]oct-3-yl; or endo-l-azabicyclo[3.3.1] non-4-yl. Representative examples are set forth in Example 6.

It is understood that these subgroups of particular interest are particularly useful in the pharmaceutical compositions and methods of treatment of this invention.

Processes for Preparing Compounds of the Invention S* The compounds of Formula I are prepared by a qa variety of methods. The synthetic approaches are apparent from the numbered dotted lines (1 to 6) in o. ,Formula I below. The dotted lines point schematically 0 to the respective reaction sites and the ensuing table gives a brief description of the various methods that 2 will be described in more detail below. The last column in the table and the letter symbols in parentheses refer to the respective step in the process claim(s).

Formula I o 4 53 3 n

S(R

2 26890-FF

U

V V -26- Approach 2.

3.

4.

6.

7.* 9.* Method Hydrogenation Formylation Al kyl1at ion N-Oxidation or Amine oxide Reduction Elabora( ion of Substituent R 1 Hydrogenation Salt Formation Liberation of Free Base Optical Resolution Separation of Diastereomers Sten *Not shown on Formula I Accordingly, the process for the preparation of a comp-ound of Formula I comprises one or more of the following steps: reactively contacting a compound of Formula II 0 9 a 96 sees

(PI),

memO e.g.

a.

CS C C R 2 q a'.

p.

004 be 0 *4 in which n, p, q, RI, R 2 and R 3 are as defined above with a formylating agent in the presence of a strong 1HVM26890-FF I P -27base to form a compound of Formula I wherein the dashed line is a double bond, reducing the double bond represented by the dashed line in Formula I by hydrogenation to form a of Formula I wherein the dashed line represents 2 hydrogens, converting a salt of a compound of Formula I to the corresponding free compound, condensing a compound of the formula R 3

L,

wherein R 3 has the above meanings and L is a leaving group with a compound of the Formula XIII,

S

O

S 15 *oig phal Xal odi a c o eXIII

(CH

2 )n CR )q wherein R 1

R

2 n, p, q, and the dashed line have the above meanings, converting a compound of Formula I to the corresponding pharmaceutically acceptable s lt, 25 oxidizing a compound of Formula 1 to form the corresponding N-oxide of the R 3 compo. of Formula I, or reducing an N-oxide of the R 3 component to the corresponding amine, reducing a R 1 nitro substituent to a R 1 amino substituent or alkylating or acylating a R 1 amino substituent or alkylating a R 1 hydroxy substituent or dealkylating a R 1 alkoxy substitutent or debenzylating a 26890-FF I t t -28-

R

1 benzyloxy substituent to the corresponding compound of Formula I, hydrogenating in positions 3a, 4, 5 and 6 a compound of the Formula XIV o

XIV

(R2 )q S. wherein R 1

R

2

R

3 p and q have the above meanings, separating a mixture of isomers or diastereemers of a compound of Formula I into a single 15 isomer or diastereomer, or conducting any of steps through with optically active reactants, In the formylation step, the compounds o Formula I 2 are prepared by the reaction sequence shown below in 0* Reaction Scheme I.

0 0 26890-FF -29- REACTION~ SCHEME I

R'-NH

2 Step I CM) 0@ U. t~ 0

S.

S S

OSS*

0000 @0 50 0

PS

0@ 0 000* 0@ S 0 0050 9000 0 0e*@ 0 S *0 S 0 *505 @0

S

S

0 1. Strong Base 2. Form y3,ating Agent Step 2 3.

(R

2 q -La Stop 3 1B 25 wherein X OH, -OR (R =alkyl) or halogen; and n, p, qt R 1

R

2 and R3 are as broadly defined above in the Summary of the Invention.

StpL In step 1 of the process of this invention, the fused-ring bicyclic acid, ester or halide of Formula III 1OHVM 2689 0-FF is reacted with an appropriate amine to form the corresponding amide of Formula II.

In general compounds of Formula III and the amines of Formula R 3

NH

2 are known in the art, are commercially available or are prepared in accordance with methods available to those of ordinary skill in the art. For example, the compounds of Formula III where X is OH, p is 1, R 1 is methoxy (particularly meta to the acid), q is 0 and n is 1 or 2 have been reported by Lowenthal, H.J. and Schatzmiller, J. Chem. SOc. Perkin Trans. I 1976; 944. Unsubstituted compounds (where p and q are both 0, and n is 1, 2 or 3) are readily available or may 0 0 be prepared in accordance with methods known in the art.

Other starting materials that are useful for preparing compounds of the invention are commercially 15 available l-cyano-4-alkoxynaphthalenes or l-cyano-2-alkoxynaphthalenes which can be hydrolyzed 00** and reduced to the corresponding starting acid of Formula III where X is OH, R 1 is 4-alkoxy or 2-alkoxy, q 2 is 0 and n is 2. Halogen-substituted tetralones are well known and are prepared from o-halo-y-phenylbutyric acids. All these tetralones can be reduced with alkali boranates such as sodium or lithium boranate to the appropriate alcohol (Formula X of Reaction Scheme II), converted to an acid and reacted with the R 3

NH

2 compound 25 as a lactone to form an amide Of Formula II according to Reaction Scheme II below. Amines of formula R 3

NH

2 that are useful in this step include those where R 3 is defined in the Summary of the Invention section of this 3 application. Particularly useful are the amines where

R

3 is one of the following radicals: 1-azabicyclo[2.2.2]oct-3-yl; l-azabicyclo[2.2.2]oct-4-yl; endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl; 26890-FF

I

-31endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl; exo-8-methyl-8-azabicylo[3.2.1]oct-3-yl; or endo-l-azabicyclo[3.3.11non-4-yl.

The reaction conditions under which Step 1 is carried )ut are those conditions that are standard for amide formation. Generally a solution of the amine in an inert organic solvent is reacted under normal conditions such as those set forth in March, J. Advanced Organic Chemistry 1985; 3rd Ed.: 370-376. A particularly useful method is the reaction of the amide as a dimethylaluminum amine (Me 2 AlNHR 3 with an alkyl Sesther (Formula III) where X is lower alkoxy, such as ethoxy. Suitable non-reactive, organic solvents toluene or dichloroethane) may be used to carry a out the reaction at mild conditions such as ambient pressure and less than ambient temperature, preferably temperatures of from about -10 0 C to about +20 0 C. The reaction generally is completed within a few hours.

Step 2 In this step the novel, intermediate amide of this invention shown as 7nrmula II is reacted with a formylating agent in the presence of a strong base.

The reaction is carried out in a non-reactive ethereal 25 solvent such as diethyl ether, dimethoxyethane or tetrahydrofuran (THF), the last being preferred.

The formylating agent useful for this reaction is any compound that achieves reaction of the amide of Formula II with the formyl group particularly a dialkylformamide, such as dimethyl formamide (DMF), diethyl formamide, etc., a N-aryl-N-alkylformamide, such as N-phenyl-N-methylformamide, etc. The formylating agent is generally used in molar excess relative to the 26890-FF r -32amide II, for example at a ratio of about 1.1 to about with 1.5 to 2.5 being preferred. The strong base useful in this reaction is one that aids the progression of the reaction and can be any appropriate alkyllithium or Grignard reagent. n-Butyllithium is particularly useful because of its availability. In general, the reaction takes place under an inert atmosphere argon) to prevent the oxidation of the alkyllithium and at a temperature range of about to ambient temperature. Preferably the temperature is about -20 0 C to about 0°C, as the reduced temperature is thought to stabilize the intermediate anions formed in this step.

Step 3 In this step the double bond (represented by the dashed line in Formula I and specifically shown in Formula IA) is reduced by hydrogenation. This reaction takes place under standard hydrogenation conditions using a standard hydrogenation catalyst under pressure varying from about atmospheric to about 2000 pounds per square inch (psi) and temperatures ranging from about ambient temperature to about 100 0 C. The hydrogenation takes place in a suitable polar, organic solvent such as 25 ethanol, DMF, acetic acid, ethyl acetate, 25 tetrahydrofuran, toluene, and the like.

While a standard catalyst rhodium on alumina, etc.) may be used, particularly useful catalysts are palladium hydroxide on carbon, 10% palladium on carbon, Pearlman's catalyst from Aldrich (50%H 2 0 20% palladium content), palladium/BaSO 4 The reduction will take place over a few hours to two or more days depending on the catalyst used, pressure, solvent and temperature.

For example using acetic acid with 70% perchloric acid 26890-FF 1 -33and 20% palladium hydroxide on carbon, a compound can be fully reduced in about 24 hours at about 50 psi and about 85 0

C.

The compound to be reduced can be used as the free base or in the form of a salt selected from the acid addition salts previously described, in particular the hydrochloride, hydrobromide, camphorsulfonate, acetate, etc. If an optically active acid is used this would frequently influence the preferential formation of one isomer.

o. Preparation of Isomers S From the Formula it is apparent that some of the compounds of the invention may have at least one or 15 two asymmetric carbon atoms (chiral centers). If the dashed line between carbon atoms 3 and 3a denotes a bond, the compounds of Formula I may have one asymmetric carbon atom in the R 3 substituent, positions 3' or 4' (which are attached to the N-atom denoted as ring atom 2).

Some R 3 substituents, for example, the 1-azabicyclo o**o [2.2.2]oct-4-yl, endo-8-methyl-8-azabicyclo[3.2.1] oct-3-yl, exo-8-methyl-8-azabicyclo[3.2.1)oct-3-yl and the endo-9-methyl-9-azabicyclol3.3.l]non-3-yl 2* substituents have no asymmetric carbon atom (center of 25 chirality). Therefore, the compounds of Formula I containing an achiral R 3 substituent and a double bond between carbon atoms 3 and 3a are achiral compounds.

S If the dashed line between carbon atoms 3 and 3a represents two hydrogen atoms, the compounds of Formula I have at least one asymmetric carbon atom, i e. the carbon atom numbered 3a. If R 3 is a chiral substituent the compounds of Formula I have two asymmetric carbon atoms.

26890-FF -34- For the compounds of Formula I which have one asymmetric carbon atom, two enantiomeric forms exist, the and form as determined by the rules of Cahn et al.

A number of methods suitable for the resolution of enantiomers can be used but the preferred methods depend on the preparation of diastereomeric compounds derived from the enantiomers. While the resolution can be achieved with covalent diastereomeric compounds derived 1 from the compounds of Formula I and diastereomeric complexes, the preferred diastereomeric compounds are dissociable. In general, the covalent diastereomers are separated by chromatography but preferred are separation/resolutio,. techniques depending on differences in solubility.

In a preferred method the compounds of Formula I with one asymmetric carbon atom are separated by the formation of crystalline diastereomeric salts between the racemic substrate S) and an optically active 2 acid. Examples of suitable resolving agents which form dissociable salts with the enantiomers of formula I are tartaric acid, o-nitrotartranilic acid, mandelic acid, malic acid, 2-phenoxypropionic acid, hydratropic acid and 2-arylpropionic acids in general, or camphorsulfonic a Sacid. Alternatively, selective crystallizat, i, direct 25 crystallization or chromotography can be used.

Specifics of the resolution techniques applicable to the e'.

preparation of enantiomers of the Formula I are described in Jean Jacques, Andr6 Collet, Samuel H.

Wilen, Enantiomers, Racemates and Resolutions, John WAley Sons, Inc. (1981).

The compounds of Formula I which have two asymmetric carbon atoms occur as diastereomeric compounds with a total of four isomers, since the first 26890-FF asymmetric carbon atom may be R or S, and so may be the second. For example the (3aR,3'R) molecule is the mirror image of the (3aS,3'S) compound, they are enantiomers. The (3aS,3'R) compound in turn is the enantiomer of the (3aR,3'S) compound. The two pairs of enantiomers stand in the relationship to each other of diastereomers, they are nonenantiomeric pairs in a set. As enantiomers the (3aR,3'R) compound and the (3aS,3'S) compound have identical physical properties 1 except that they rotate the plane of polarized light in equal amounts in opposite directions. In addition, they react at different rates with other optically active compounds.

The properties of the enantiomers of one *1 diastereomeric pair, however, are not identical with those of the other diastereomeric pair. In other words, the (3aS,3'S) compound has different physical properties from the (3aR,3'S) and the (3aS,3'R) compound. They have different melting points, boiling points, 2 solubilities, reactivity and other properties.

Since the nonenantiomeric pairs that make out the diastereomers have different melting points, boiling points, and solubilities, the pairs can be easily separated by conventional means such as salt formation S that allows to apply crystallization techniques based 25 upon differences in solubility. However, the free bases or their salts that form diastereomers can also be separated by chromotographic techniques. Since the 4 diastereomers have different physical properties, no optically active auxillary reagents such as resolving agents need to be employed. For salt formation all the salt-forming acids described above, as long as they form crystalline salts, may be used for the separation techniques. A particular advantage of chromatographic 26890-FF I -36resolutions is that they provide both diastereomers generally in a state of high purity. Every type of preparative chromatography can be used for the purpose of such diastereomer separation (gravity column, thin-layer, dry-column and high- and medium-pressure liquid chromatography). Specifics of the applicable methodology are described in Jean Jacques, Andr6 Collet, Samuel H. Wilen, Entiomers, Racemates, an Resolutions, John Wiley Sons, Inc. (1981), Chapter After separation of the two pairs of enantiomers each pair can be resolved into its enantiomers by the methods generally used for the separation of enantiomers, resolution by direct crystallization

*W

which depends on differences in the rates of crystallization of the enantiomers in a supersaturated solution with respect to the racemate. Alternatively, resolving agents and fractional crystallization can be empli4Ad as described for the compounds of Formula I with one asymmetric carbon atom.

Alternatively, the compounds of the invention may be prepared using optically active reactants. For example, using (R)-or (S)-amines of the Formula R 3

NH

2 (wherein R 3 has the above meanings) individual isomers of the Formula II may be prepared which may be converted S to individual isomers of Formulae IA or IB. This is 25 shown by Examples 1A(2), 2A for the amides of Formula II and by Examples 4A(2), 5A,CD for the compounds of Formula IA and by Example 7 for the compounds of Formula S" IB.

The stereoconfiguration at the chiral centers of the compounds of Formula I can be assigned by circular dichroism, preferably by Single Crystal X-Ray Analysis.

26890-FF i I -37- Other Methods of Preparation One of ordinary skill in the art will also recognize that a compound of Formula I may be prepared as an acid addition salt or as the corresponding free base. If prepared as an acid addition salt, the compound is converted to the free base by treatment with a suitable base such as ammonium hydroxide solution, sodium hydroxide, potassium hydroxide or the like. When converting a free base to an acid addition salt, the compourv is reacted with suitable organic or inorganic acid (described earlier).

,o It is also understood that compounds of this invention that are the N-oxides of compounds of -rmula I (the N-oxides of the cyclic amin.e portion of

R

3 are prepared by means kiown in the art by reacting a I compound of Fortula I with oxidizing agents such as Se.

pertrif li. 'roacetc acid, permaleic acid, perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid. With m-chloropezoxybenzoic acid the oxidation is conducted 2 under cooling in an inert, organic solvent such as a halogenated hydrocarbon, e.g. dichloromethane. For this oxidation to take place effectively, the compound of Formula I is preferably in the free base form.

The N-oxides of the compounds of Formula I can also be reduced by methods known in the art. A number of reducing agents are suitable for this purpose, specifically sulfur dioxide, sulfur itself, triaryl phosphines such as triphenyl phosphine, alkali boranates a such as lithium or sodium boranate, or phosphorous trichloride or tribomide. The reaction will be conducted at a temperature between 0 and 80°C, with gradual raising of the temperature and the reaction mixture is occasionally shaken. As some of the N-oxides have a 3ow melting point the reduction can be conducted 26890-FF -38without an additional solvent. If a solvent is be'.ng used then the following solvents are preferred: acetonitrite, ethanol, or aqueous dioxane.

Because of the hazardous nature of many of the reducing agents or of the reaction products, the preparation should be conducted in a closed system to avoid exposure to irritating fumes.

The condensation of the compounds of the formula

R

3 L wherein R 3 has the above meanings and L is a leaving 0group (halogen, mesyloxy, benzenesulfonyloxy, ethanesulfonyloxy or tosyloxy) with a compound of the Formula XIII is carried out under the usual amide alkylating conditions. The amides of Formula XIII are very weak bases. In order to activate the amides, they must first be converted to their anions in order to increase their reactivity. This is effected with strong bases such as sodium, preferably sodium hydride but also alkyl alkali compounds such as butyl lithium, and by adding the alkylating agent R 3 L. Because the alkylation Sinvolves the release of the acid HL, one usually employs 20 the strong base in stoichiometric excess. The o alkylation is generally carried out in an inert solvent at a temperature between 20 and 100 0 C. The following inert solvents are employed: N, N-dialkylformamides such as N,N-dimethylformamide or tetahydrofuran.

Alternatively, the alkylation can bo carried out by phase-transfer catalysis. The reaction can be carried out in a conventional catalytic two-phase system comprising a concentrated alkali hydroxide solution as the aqueous phase and a non-aqueous phase comprising an inert solvent for the product. The reactior is effected 26890-FF -39with an alkylating agent RRBr used in 10 to 50% excess added slowly to the system containing a phase-transfer catalyst such as tetra-n-butyl-aminium hydrogen sulfate. The liquid-liquid two-phase system can be replaced with a solid-liquid system comprising powdered alkali hydroxide/alkali carbonate suspended in an inert solvent in the presence of a phase-transfer catalyst such as tetra-n-butylaminium hydrogen sulfate. In both instances the reaction mixture is kept at reflux after 1 addition of the alkylating agent until the reaction is completed. The resultant mixture is cooled to room temperature and the compound of Formula I isolated after S separation of the organic phase or by other conventional methods such as extraction. Details of the procedure 15 are described in Synthesis, Communications 1005 (1981).

The amides of Formula XIII are obtained by the formylation method described for step above.

The compounds of Formula I with R 1 hydroxy, nitro, or amino substituents can be converted to other R 1 substituents in a manner known per se. The R 1 nitro group can be converted to an amino group by a number of well-described methods, either the metallic reducing agents such as zinc, tin or iron and acid, catalytic hydrogenation, sulfides such as sodium hydrogensulfide, 25 ammonium sulfide, complexes of aluminum trihydride with aluminum chloride or hydrazine and a catalyst.

C.

Specifically useful methods are described by Joffe, Tartakovskii, and Novikov, Russ. Chem. Rev. 35, 19-32 (1966).

The resulting amino compounds in turn can be alkylated or acylated. The alkylation is conducted with alkyl halides, sulfates, such as dimethyl sulfate or sulfonates. The amino compounds can also be acylated in a manner known per se with acyl halides, anhydrides, 26890-FF esters or with acids. The conditions follow that of the well-known Schotten-Baumann procedure. Frequently aqeuous alkali is added to combine with the liberated hydrogen halide. If acids are being used the reaction is made to proceed in good yield at room temperature with dehydrating agents such as dicyclohexylcarbodiimide or N,N'-carbonyl diimidazole. The acylation can also be carried out as anhydrous coupling of the acid chloride with the free base in a suitable organic solvent 1 (toluene, tetrahydrofuran, ethyl acetate) with good mechanical stirring.

The compounds of Formula I with R 1 being alkoxy can also be prepared from the compounds with R 1 being a *efe hydroxy group by alkylation. The reaction proceeds quickly with diazo compounds such as diazomethane under 15 000 mild conditions with high yields. The best method, however, is the Williamson reaction which is carried out in the presence of a base.

The hydrogenation of the compounds of Formula XIV to the compounds of Formula I can be effected by methods known for the partial hydrogenation of aromatic compounds.

The compounds of Formula XIV are prepared by heating a mixture of an optionally sub' ituted 25 1,8-naphthalic acid anhydride and an amine of the formula R 3

NH

2 in an inert solvent at 80 to 200 0 C until Se completion, preferably in the presence of a dehydrating agent such as an anhydride or diimide, followed by reduction of the carbonyl group at the 3-position of the benz[de]isoquinoline-l,3-dione derivative with alkali boranates. The hydrogenation of the compounds of Formula XIV to the compounds of Formula I is effected by methods known to convert naphthalene derivatives to tetralines. The compounds of Formula I with R 1 being hydroxy are prepared by dealkylation or debenzylation of 26890-FF -41starting materials of the Formula I with R 1 being either alkyloxy or phenylalkyloxy, in particular benzyloxy.

The dealkylation is carried out preferably by acid cleavage of the alkyl aryl ether, preferably with hydrogen iodide or hydrogen bromide. Other suitable cleaving agents are Lewis acids such BF 3 BCl 3 BBr 3 or A1C1 3 or anhydrous sulfonic acids or Grignard reagents.

If HBr or HJ are used the reaction is generally carried out with the acid addition salt of the alkyl aryl ether using an excess of cleaving agent without a solvent at elevated temperatures, 4QOC to the boiling point of the reaction mixture, preferably 60 to 95 0

C.

0 The debenzylation is carried out around room e temperature under hydrogen with a palladium, platinum or rhodium catalyst with the benzyl aryl ether in solution in an inert sol7ent. Frequently the catalyst is removed by filtration for recovery and regeneration.

Accordingly, therapeutically active compounds of this invention are especially prepared by reacting an amide of Formula II with a formylating agent in the presence of a strong base to form a compound of Formula IA, hydrogenating a compound of Formula IA to form a compound of Formula IB, 25 converting an acid addition salt of a compound of Formula I to the corresponding free base, 0" converting a free base of a compound of Formula I to the corresponding pharmaceutically 50 acceptable salt, oxidizing a compound of Formula I to form the corresponding N-oxide of the R 3 component of Formula I, or 26890-FF S 4 -42separating a mixture of isomers of a compound of Formula I into a single isomer.

In any of the above last step processes, a reference to Formula I, IA, IB, or II refers to such Formulae wherein n, p, q, R 1

R

2

R

3

R

4

R

5 u, x, y, and z are as defined in their broadest definitions set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments.

PREPARATION 1 A. This preparation presents a generic description of a method for preparing compounds of SFormula II (particularly where q is which compounds are useful as intermediates for the preparation of compounds of Formula I of this invention. In general, the process involves three steps.

REACTION SCHEME II

S

S@

S S

*SS*

S S 0S S

S

5 Sr US S R2)q

X

S.~i 55 S S 2. XI I R I

CIR

2 )q

XIX

3. XII 26890-FF V A 0 -43- While this 3-step process may be used to prepare compounds of Formula II (and thus Formula I) where p, n,

R

1 and R 3 are broadly defined, it is particularly useful for preparing compounds of Formula II where n is 3 and p is 0.

In Step 1, an alcohol of Formula X is reacted with with a strong base such as an alkyllithium n-butyllithium) at elevated temperatures to form an intermediate anion. The reaction takes place in a suitable, inert organic solvent such as an alkane, e.g.

hexane generally at reflux temperature for a period of time sufficient to form the intermediate. Then carbon dioxide is bubbled through to complete the reaction 00 :(about 5 hours) and form the lactone of Formula XI.

In step 2, the resulting lactone is reacted with an 5 15 amine of the Formula R 3

NH

2 under conditions similar to m* those discussed hereinbefore regarding amide formation f*s from an ester of Formula III in Reaction Scheme I.

In step 3, the resulting hydroxy amide is reduced to form a compound of Formula II under standard reduction (hydrogenation) conditions using a standard reducing catalyst such as 20% palladium hydroxide on carbon.

2 B. 2,6,7,8,9,9a-HEXAHYDROCYCLOHEPT[cd]ISOBENZO- 25 FURAN-2-ONE (A compound of Formula XI wherein n 3 and p 0).

S.C

To a solution of 5,6,7,8-tetrahydro-9Hbenzocyclohepten-9-ol (4.03 g, 31.9 mmol) in hexane (100 ml) heated under reflux was added dropwise during a minute period, a 2.5 molar solution of n-butyllithum in hexane (32 ml, 80.0 mmol). After being heated under reflux for 20 hours, the stirred mixture was cooled to 26890-FF -44- 0 C and dry carbon dioxide was bubbled through for 5 h, during which time a white precipitate separated. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate. The aqueous solution was adjusted to pH 2.0 with concentrated hydrochloric acid while being stirred in an ice-water bath. The resulting precipitate was filtered and recrystallized from hexane to afford 2,6,7,8,9,9a-hexahydrocyclohept[cd]isobenzofuran-2-one (2.63 m.p. 84-85 0

C.

For a further exemplification of these steps see Example 3.

SEXAMPLE 1 EAPREPARATION OF COMPOUNDS OF FORMULA II WHEREIN n IS 1.

15 A. N-(l-AZABICYCLO[2.2.2]0CT-3-YL)-4-INDAN- CARBOXAMIDE (A compound of Formula II wherein n 1, p q 0, and R 3 1-azabicyclo[2.2.2]oct-3-yl) soot From ethyl 4-indancarboxylate (Formula III wherein X OC 2

H

5 Reaction Scheme I, Step 1) A solution of (RS)-3-amino-l-aza- 25 bicyclo[2.2.2]octane (1.51. g, 12 mmol) in toluene (20 ml) was added dropwise to a stirred solution of trimethylaluminum (12 mmol) in toluene (6 ml), so that the temperature did not exceed 10 0 C. The mixture was

S.

stirred for 30 minutes, and a solution of ethyl 4-indancarboxylate (2.16 g, 11.3 mmol) in toluene (20 ml) was gradually added. The reaction mixture was heated under reflux for 16 hours, then cooled to room temperature. The reaction mixture was added at 00 C to aqueous hydrochloric acid 20 ml). After separation 26890-FF of the layers, the aqueous layer was made basic with 10 N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried with anhydrous potassium carbonate, filtered and evaporated to afford 52.42 g of a white solid. A sample recrystallized from ulthyl acetate gave (RS)-N-(l-azabicyclo[2.2.2]oct-3-yl)-4-indancarboxamide, m.p. 158-158.5 0 C. Anal.: Calcd. for C 17

H

22

N

2 0: C, 75.52; H, 8:20; N, 10.36. Found: C, 75.95; H, 8.22; N, 10.50.

By following the above procedure of Part but substituting or (R).-3-amino-l-azabicyclo[2.2.2]octane for the (RS) mixture, one obtains (S)-N-(1-azabicyclo[2 2Ioct-3-yl)-4-indancarboxamide 15 (60% yield), m.p. 159-160 0 C; [a1D 25 -47.5- (c 0.4, CHCl 3 or(R)-N-(1-azabicyclo[2.2.2]oct-3-yl)-4-indancarboxamide.

B. Other 4-indancarboxarnides of Fotiqula II where n is 1 and R 3 is another substitutent.

following the procedure of part A(l) of this .0.:..example but changing (R)3aiolaaicco222otn to (R--amino-l-azabicyclo[2.2.2]octane t no--aiabicyctll2 .2lctane; 3llonne 25endo-3-amino-9-methyl-9-azabicyclo ontane; eno-3-amino-8-methyl-8-azabicyclo octane; o endo-4-amino-l-azabicyclo nonane; the following compounds of Formula (II) are respectively prepared: N-(l-azabicy".lo[2.2.2]oct-4-yl)-4-idancarboxamfide; NV-(endo-9-methlyl-9-azabicyclo[3.3 .llnon-3-yl)-4-indancarboxamide; l0HV'M 1 HVM26890-FF -46- N-(endo-8-methyl--8-azabicyclo[3.2.l]oct-3-yl)-4-indancarboxarnide; N-(exo-8-methyl-8--azabicyclo[3.2.lloctu-3-yl)-4-indancarboxamide; or N-(endo-l-azabicyclo[3.3.l)non-4-.%l)-4-indancarboxamide.

C. 5-Methoxy-N-(1 -azabicyclo2(2.2.] oct-3-yl) indancarboxamide.

By following the procedure of Part A(1) or A(2) of this Example, but substituting ethyl 5-methoxy--4-indancarboxylate for ethyl 4-indancarboxylate, one obtains (1RS)-5-methoxy-N--(l-azabicyclol2.2.2i]oct-3-yl)-4-indancarboxamide or the respective or (R)-isorner.

*EXAMYPLE 2 PREPPRATION OF COMPOUN'DS OF FORMULA II WHERE n IS 2.

A. (S)-N-(l-AZABICYCLO[2.2.2]OCT-3-YL)- 5, 6,7, (-TETRAHYDRO-l-NAPHTHALENECARBOXAMIDE (A compound of Formula II wherein n p q =0 and R3 (s)-3)--azabicyclo[2.2.2]oct-3-yl) From~ 5,6,7, 8-tetrahydro-l-napbth~lene- 25 carboxylic acid. (Formula III wherein X OH, Reaction Scheme I, Step 1) A solution of 5,6,7,8-tetrahydro-l-naphthalenecarboxylic ac~id (Ofosu-Asante, K. and Stock, L.M., J. Org. Qhem 1986; 51: 5452) (2.06 g, 11.7 mmol), oxalyl. chloride (1 ml, 11.7 mmoi), and dimethylforrnamide (0.1 ml) in dichlorornethane (20 ml) was stirred at room temperature for one hour. The mixture was then concentrated under reduced pressure, and the residue was 1HVM26890-FF -47dissolved in dichloromethane (20 ml). The resulting solution was added dropwise at OOC to a solution of (S)-3-amino-l-azabicyclo[2.2.2]octane (1.48 g, 11.7 mmol) in dichloromethane (20 ml). The solution was stirred at room temperature for 30 minutes, and the solvent was evaporated under vacuum. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was basified with NH 4 0H and extracted with dichloromethane. The dichloromethane was dried with anhydrous potassium carbonate, filtered and then evt3poeated to afford 2.75 g of white crystals. A sample =u recrystallized from ethyl acetate/hexane gave -(l-azabicyclol2.2.2]oct-3-yl)-5,6,7,8-tetrahydrol-napthalenecarboxamide, 159-160 0

C;

he 1 10c] D25 -42.10 (c 0.65, CHCl 3 B. Other 5,6,7,8-tetrahydro-l-naphthalenecarboxamides of Formula II where n is 2 and R 3 is another substituent.

0 By following the procedure of Part A of this Example 2, but changing (S)-3-amino-l-azabicyclo[2.2.2]octane to 3 4-amino-l-azabicyclo octane; endo-3-amino-9-methyl-9-azabicyclot3.3.l nonane; endo-3-amino-8-methyl-8-azabi\rcyclo [3.2.1]octane; exo-3-amino-8-methyl-8-azabicyclo[3.2.loctane; or endo-4-amino-l-azabicyclo[3 .3 .lnonane; the following compounds of Formula (II) are respectively prepared: N-(l-azabicyclo[2.2.2]oct-4-yl)-5,6,7,8-tetrahydro- 1-naphthalenecarboxamide; N-(endo-9-methyl-9-azabicyclo[3.3.l non-3-yl)- 6,7,8-tetrahydro.-l-naphthalenecarboxamide; 26890-FF 1 0 -48- N-(endo-8-nethyl-8--azabicyclo[3 lloct-3-yl)- 5,6,7, 8-tetrahydro--l-naphthalene carboxamide; 5,6,7, 8-tetrahydro-l-naphthalenecarboxamide; or N- (endo-l-azabicyclo [3.3.13 non-4-yl) 8-tetrahydrol-naphthalenecarboxamide.

C. 2-Methoxy-, 4-methoxy-, and 4-benzyloxy- N-(i-azabicyclo[2.2.2]oct-3-y1)-5,6,7,8-tetrahydro- 1-naphthalenecarboxamide.

00 VeBy following the procedure of Part A of this Example 2, but substituting 2-methoxy--5,6,7,8-tetrahydro- 1-naphthalenecarboxylic acid for 5,6,7,8-tetrahydro- :4 l-naphthalenecarboxylic acid, one obtains *..,(S)-2-rnethoxy-N-(l-azabicyclo[2.2.2]oct-3-yl)- S...0 5,6,7, 8-tetrahydro--l-naphthalenecarboxamide, m.p. 270-271.

0 C, its 4-methoxy-isomer and (S)-4-benzyloxy-N-(l-.azabicyclo[2.2.2]oct-3-yl)- 5, 6, 7, 8-tetrahydro-l-naphthalenecarboxamide.

4-Chloro--N-(l-azabicyclo[2.2.2]oct-3-yl)- 5,6,7, 8-tetrahydro-1-naphthalenecarboxaride.

0 25 By folIlowing the procedure of Part A of this Example 2, but substituting 4-chloro-5,6,7,8-tetrahydrol-naphthalenecarboxylic acid for 5,6..7,8-tetrahydros~ l-naphthalenecarboxylic acid, one obtains (S)-4-chloro-N(l-.azabicyclo[2.2.2loct-3-yl)- 5, 6, 7,8-tetrahydro-l-naphthalenecarboxamide.

E. N-(ENDO-9-METHYL--9-AZABICYCLOL3 lINON-3-YL)- 6, 7,8-TETRAHYDRO-1-N1APHTHALENECARBOXAMIDE (A compound IOHVM ]OHVM2689 0-FF f I -49of Formula 11 wherein n 2, p q 0 and R3 endo-9--methyl-9-azabicyclo[3 1]non-3-yl) A solution of 5,6,7,8-tetrahydro-1-napthalenecarboxylic acid (571 mg, 3.24 rumol), oxalyl chloride (0.44 ml, 5.0 mmol), and dimethylformamide (0.05 ml) in dichloromethane (20 ml) was stirred at room temperature for one hour. The mixture was then concentrated under reduced pressure and the residue was dissolved in toluene (10 ml). The resulting solution was added dropwise to a stirred mixture of endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (500 mg, 3.24 mmol) and sodium carbonate (700 mg, 6.5 mmol) in 5 ml water and 25 ml *toluene. After 2 hours the mixture was diluted with :ethyl acetate (100 ml). The layers were separated and ***the organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 700 mg of white crystals. A sample recrystallized from ethyl acetate gave N-(enio-.9-metiiyl- 9-azabicyclo[3.3.1]non-3-yl)-5,6,7,8-tetrahydro- 1-naphthalenecarboxamide, m.p. 1.66-1J67 0

C.

EXAMPLE 3 PREPARATION OF COMPOUNDS OF FORMULA II WHERE n 1S 3.

(RS)-N-(l-AZABICYCLO[2.2.2JOCT-3-YL)- 5,6,7, 8-TETRAYDRO-9H-BENZOCYCLOHEPTEN-1CARBOXAMIDE compound of Formula 11 wherein n 3, p =q and -azabicyclo[2.2.2joct-3-yl; Reaction Scheme II, Steps 2-3) A solution of (RS)-3-.amino-1-azabicyclo[2.2.2]octane (1.00 g, 8 mmol) in toluene (20 ml) was added dropwise to a stirred solution of IOHVM 1HVM26890-FF t I I trimethylaluminum (8 mmol) in toluene (10 ml), so that the temperature did not exceed 10 0 C. The mixture was stirred for 30 minutes, and a solution of 2,6,7,8,9,9a-hexahydrocyclohept[cd]isobenzofuran-2-one (Preparation IB) (1.25 g, 6.6 mmol) in toluene (10 ml) was gradually added. The reaction mixture was heated under under reflux 0.5 hours and then cooled to ambient temperature. Water was added gradually until a solid was precipitated, and the mixture was filtered. The solid was washed with ethyl acetate and the combined organic layer was evaporated to afford (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-9H-9-hydroxy- 5,6,7,8-tetrahydrobenzocyclohepten-l-carboxamide (1.42 g, 68% yield). Crystallization from ethanolic hydrochloric acid afforded the hydrochloride salt, m.p. 239 0

C.

Reduction of (RS)-N-(l-azabicyclo[2.2.2]oct-3-yl)o. 9H-9-hydroxy-5,6,7,8-tetrahydrobenzocyclohepten- 1-carboxamide (1.42 g, 4.5 mmol) in ethanolic hydrochloric acid (20 ml) with 20% palladium hydroxide on 2 carbon (0.5 g) was carried out at 50 psi for 24 hours.

The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Puritication of the product by column chromatography (10% methanol in methylene chloride and 1% ammonium hydroxide) afforded (RS)-N-(l-azabicyclo[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro- 9H-benzocyclohepten-l-carboxaide (0.52 g, 39% yield).

B. Other compounds of Formula II where n is 3 and R 3 is another substituent.

By following the procedure of Part A of this Example 3 but changing (RS)-3-amino-l-azabicyclo[2.2.2]octane to 4-amino-l-azabicyclo[2.2.2]octane, 26890-FF 1endo-3-amino--9-methyl-9-azabicyclo[3.3. 1noiane, endo-3-amino-8-methyl-8. azabicyclo 13 octane, exo-3-amino-8-methyl-8-azabicyclo[3.2.lloctane, or endo-4-amino-l-azabicyclo [3 1] nonane, the following compounds of Formula (II) are respectively prepared: N-(J.-azabicyclo[2 .2 .2Ioct-4-yl)-5, 6, 7,8-tetrahydro- 9H-benzocyclohepten-l-carboxamide;4 N-(enaio-9-methyl-9-azabicyclo[3.3.llnon-3-yl)- 5,6,7,8-tetrahy,,dro-9H-benzocyclohepten-l-carboxa~iide; N-(endo-8-rnethyl-9-azabicyclo [3 lloct-3-yl)- 6,7, 8-t~trahydro-9H-benzocyclohepten-l.-carboxamide; a N-(exvo-8-methyl-9-azabicyclot3.2.lloct-3-f1)- 5,6,7, 8-tetrahydro-9H-benzocyclohepten-l-carboxamide; or N- (endo-l-azabicyclo 13.3.11 oct-3-yl) 8-tetrahydro- ~9U1-benzocyclohepten-l-carboxamide.

EXAMPLE A PREPARATION OF COM4POUNDS OF FORMULA I WHERE n IS 1 AND THE DASHED LINE IS A BOND.

A. 2-(l-AZABJICYCLO[2.2.2]OCT-3-yl)-le2,4, TETRAHYDROCYCLOPN'i"L dcej I SOQU INOL IN -I -ONE (A compound of aFormula IA whereir a 1, p =q and

R

3 -azabicycj'o[2.2.2]oct-3-yl; Reaction Scheme I, Step 2) A solution of (RS)-.N-(l-azabicyclo[2.2.2]octa 'a 3-yl)-4-inaancarboxamide (Example 1) (2.07 g, 7.7 nunol) in dry tetrahydrofuran (100 ml) at -70 0 C was treated with n-butyllithiun (20 mol). The reaction mixture was stirred at -l0OC for one hour, cooled to -70 0 C, and dirnethylfo~rramide (15 mxnol) ac 9 3ed in one portion, The reaction mixture was allowed to warm to room temperature InHVM 11HVM26890-FF -52over 1.5 hours, then cooled to 0 0 C and acidified with aqueous hydrochloric acid. The layers were separated, and the aqueous layer was washed with ethiyl acetate, then made basic with 10 N aqueous sodium hydroxide and extracted with ethyl acet .te. The ethylacetate was dried over anhydrous sodium sulfate, filtered, and evaporated to afford 1.75 g (81% yield) of white crystals. A sample recrystallized from ethyl acetate gave (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)- 1,2,4, 5-etrahydrocyclopent [ce] isoquinolin-1-one (Compound m-p. 146-147 0 C. Anal.: Calcd, for 0069C 18

H

20

N

20 C, 77.11; 7.19; N, 9.99%. Found: C, 76.93; H, 7.23; N,9.90%.

The hydrochloride salt monoethanol adduct was prepared from ethanol-HCl: In.p.

188-1L90 0 C. Anal.: Calcd. for C 18

H

20

N

2 0-HCl'C 2

H

5 0H: C, 66.19; H, 7.50; N, 7.72%. Found: C, 66.08; H, 7.55; N, 7.6,5%.

By following the above pr-ocedure but substituting the (S)-isomer of N-(l-aza-.bicyclo[2.2.2I]oct-3-yl)-4-.indancarboxamide for Cs" the (RS)-mixture, one obtains (S)-2--(l-azabicyclo[2.2.2]oct-3--yl)-1,2,4,5-tetrahydro- 25cyclopent~delisoquinolin-1-one (Coattound B) (50% yield).

A sample recrystallized from ethyl acetate had a m.p. 155.5-156*C.; SCC 2 +47.10 (c 0.41, CHC1 3 Anal.: Calcd. for C,0 20 2 0: C, 77.11; H, 7.19, N, 9.99%. Found: C, 77.45; H, 7.12; 9.84%.

The hydrochloric acid salt [Compound B was prepared from ethanol-HCl: m.p. >285 0 C; [a1D 25 -12.80; Anal.: Calod. for C 18

H

20

N

20 .HCl.0.5 H 2 0: C, 66.35; H,.6.81; I'V, 8.59%. Found: C, 65.96; H, 6.86; N, 8.33%.

IOHVM 1 0HV~4 2689 0-.FF -53- (R)-2-(l-azabicyclo[2.2.2]oct-3-yl)- 1,2,4,5-tetrahydiocyclopent[de]isoquinolin-l-one is similarly prepared as the hydrochloride [Compound W (LHCL m.p. >285°C; 25 D 17.1 (H20, C 0.6).

B. Other 1,2,4,5-tetrahydrocyclopent[de]isoquinolin-1-ones of Formula II where n is 1 and R 3 is another substituent.

By following the procedure of Part A(1) of this Example 4, but substituting other compounds of Example IB and IC for 44 (RS)--N-(l-azabicyclo2.2.2.]oct-3-yl)-4-indancarboxamide, on obtains the corresponding compounds of Formula I.

EXAMPLE PREPARATION OF COMPOUNDS OF FORMULA I WHERE n IS 2 AND THE DASHED LINE IS A BOND.

A. (S)-2-(1-AZABICYCLO[2.2.2]OCT-3-YL)- 2,4,5,6-TETRAHYDRO-1H-BENZ[de]ISOQUINOLIN-1-ONE (A compound of Formula IA wherein n 2, p q 0, and

R

3 l-azabicyclo[2.2.2]oct-3-yl; Reaction Scheme I, Step 2) 2 A solution of n-butyllithium in hexane (60 mmol) was added dropwise at -70 0 C to a solution of -azabicyclo[2.2.2 oct-3-yl)-5,6,7,8-tetrahydrol-naphthalenecarboxamide (Preparation 1) (7.10 g, 21 mmol) in dry tetrahydrofuran (400 ml). The reaction mixture was stirred at -10 0 C for one hour, cooled to and dimethylformamide (100 mmol) added in one portion. The reaction mixture was allowed to warm to room temperature over 1.5 hours, then cooled to 0°C and S acidified with 10% aqueous hydrochloric acid. The layers 26890-FF -54were separated, and the aqueous layer was washed with ethyl acetate, then made basic with 10 N aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7.58 g (95% yield) of (S)-2-(l-azabicyclo[2.2.2Ioct-3-yl)-2,4,5,6-tetrahydro- 1H-benz[deIisoquinolin-l-one (Compound C) as white crystals; m.p. 117-118OC; D25 +43.20 (c 0.98, CHCl 3 Crystallization from ethanolic hydrochloric acid afforded 9.75 g of the hydrochlorile salt monoethanol adduct (Compound C (HC1)] as white crystals, m.p. )27U 0

C,

1c0D]25 -8.40 (c 2.4, H 2 Anal.: Calcd. for

C

19

H

2 2

N

2 0'HCl*C 2 HOH: C, 66.91; H, 7.75; N, 7.43%.

6* Found: C, 66.77; H, 7.65; N, 7.27%.

060S *0000 15 Crystallization from isopropanolic HCl provided the *r unsolvated hydrochloride salt.

0SSO Similarly prepared was (RS)-2-(l-azabicyclo[2.2.2i1 es..

oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[delisoquinolin-l-one; m.p. LHC1 salt; Compound D (HCWJ 176-177 0

C.

Similarly prepared was (R)-2(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro- LH.-benz (del isoquinolin-l-one; m.p. >275 0

C;

m] D 25 (HCl salt) [Compound E (HQI) +6.80 (c 2, H 2 0).

25499 B. 2-(ENDO-9-METHYL-9-AZABICYCLO[3.3.1]NON- 3-YL) 6-TETRAHYDRO-lH-BENZ [de ISOQUINOLIN-l-ONE (A compound of Formula IA wherein n 2, p q 0 and 6 R 3 endo--9-methyl-9-azabicyclol3.3. ]non-3-yl; Reaction Scheme I, Step 2) A solution of n-butyllithium in hexane mmol) was added dropwise at -70 0 C to a solution of 2-(e.ndo-9-methyl9-azabicyclo[3.3.llnon-3-yl)- 26890-FF 5,6, 7,8-tetrahydro-l-napththalenecarboxamide (Example 2B) (0.7 g, 2.24 mmu-ol) in dry tetrahydrofur.m, (25 ml).

The reaction mixture was stirred at -10 0 C for one hour, cooled to -70 0 C, and dimethylformamide (13 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature over 1.5 hours, then cooled to 0 0 C and acidified with 10% aqueous hydrochloric acid.

The layers were separated, and the aqueous layer was washed with ethyl acetate, then made basic with concentrated ammnonium hydroxide and extracted with ethyl acetate (100 ml). The ethyl acetate was dried over anhydrous sodium sulfate, filtered, and evaporated to o afford 2-(enco-9-methyl-9-azabicyclo[3.3.llnon-3-yl)- 2,4, 5, 6-tetrahydro-lH-benz [del isoquinolone-.1-one.

~The hydrochloride salt [-Compound F (HQl) I was prepared *e from ethanolic HCl; m.p. 236 0 C. Anal. Calcd. for

C

2 1 11 2 7 C1N 2 0*H 2 0: C, 66.92; H, 7.75; N, 7.43%. Found: 00OU C 66.45; H, 7.79; N, 7.32%.

By following this procedure but substituting other l-naphthalenecarboxamides of Example 2B for 2-(endo-9-methyl-9-azabicyclo[3 .3 .llnon-3-yl)- 6,7, 8-tetrahydro-l-naphthalenecarboxamide, the following compounds are prepared: 2-(1-azabicyclo[2.2.2]oct-4-yP)-2,4,5,6-tetrahydro- *1H-benz [del isoquinolin-l-one, m.p. [HCl salt; Compound G I. (HCl)] 335-337 0 C;2-(endo--8-methyl-8-azabicyclo[3.2.1] oct-3-yl)-2,4,5,6-tetrahydro-lH-benz[de]if-oquinolin-l-one; m.p. [HCl salt; Cgm-pound H (HC1)] 269-2700; 2-(exo-8-methyl-8-azabicyclo[3.2.lloct-3-yl)- 2, 4, 5,6-tetrahydro--1H-benz (del isoquinolin-l-one; m.p. [HCl salt; Comygunid I (HCl)J )270 0 C; and 2- (endo-1-azabicyclo non-4-yl) 6-tetrahydro- 1HVM26890-FF lH-benz I delisoquinolin-1-one; rn.p. [HCl salt; Compound J (HC1)] >360 0

C.

C. (S)-2-(l-azabicyclot2 .2 .2Ioct-3-yl).-9-rnethoxy- 52 ,4 S-tetrahydro-1H-benz ide] isoquinolin-1--one.

By following the procedure of Part A of this Example 5, but substituting the compound prepared in Example 2C, one obtains (S)-2-(l--azabicyclo[2.2.2]oct-3-yl)-9--methoxy- 2 6-tetrahydro-lH-benz iide] isoquinolin-l-one.

D. (S)-2-(l-Azabicyclol2.2.2Iloct-3--yl)-7-chloro- 2,4,5, 6-tetrahydro-lH-benz ide] isoquinolin-l-one.

By following the procedure of Part A of this Example 5, but substituting the compound prepared in @Goo Example 2D, one obtains (S)-2-(l--azabicycloi2.2.2]oct-3-yl)-7-chloro- 2,4,5,6-tetrahydro-lH--benz~delisoquinolin-l-one.

s EXAMPLE6 *PREPARATION OF COMPOUNDS OF FORMULA I WHERE n IS 3 AND THE DASHED LINE REPRESENTS A BOND.

A. (RS)-2-(l-AZABICYCLO[2.2.2]OCT-3-YL)- 1,2,4,5,6, 7-HEXAHYDROCYCLOHEPT [deiISOQUINOLIN-l-ONE (A compound of Formula IA wherein n 3, p q 0 and R 3 S. =1-azabicyclo[2.2.2]oct-3-yl; Reaction Sch "n e 1, Step 2) A solution of n-butyllithium in hexane (2.7 mmol) was added dropwise at -70 0 C. to a solution of (RS) 1-azabicyclo [2.2.21 oct.-3-yl) 8-tetrahydro- 1HVM26890-FF -57- 9H-benzocycloheptene-l-carboxamide (Example 3A) (0.37 g, 1.2 rmol) in dry tetrahydrofuran (10 ml). The reaction mixture was stirred at -10C for one hour, cooled to 0 C, and dimethylformamide (1.5 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature over 1.5 hours, then cooled to OOW and acidified with 10% aqueous hydrochloric acid. The layers were separated, and the aqueous layer was washed with ethyl acetate, then made basic with aqueous ammonium hydroxide. The ethyl acetate was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to afford 0.15 g (40% yield) of (RS)-2 -(l-azabicyclo-[2.2.2]oct-3-yl)- 9 1,2,4,5,6,7 -hexahydrocyclohept[de]isoquinolin-l-one as a 0:00 foam. The hydrochloride salt [Compound K was 15 0 9. prepared from ethanol-HC; m.p. >285 0

C.

.9.9 B. Other compounds of Formula I where n is 3 and

R

3 is another substituent.

sees By following the procedure of Part A of this Example 6, but changing (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro- 9 H-benzocycloheptene-1-carboxamide to: 999.9, N-(l.-azabicyclo[2.2.2]oct-4-yl)-5,6,7,8-tetrahydrol-naphthalenecarboxamide; :0 N-(endo-9--methyl-9-azabicyclo[3.3.l non-3-yl)- 5,6 8-tetrahydro-l-naphthalenecarboxamide; N-(endo-8-methyl-8-azabicyclo E3 oct-3-yl) 5,6,7,8-tetrahydro-l-naphthalenecarboxamide; N-(exo-8-methyl-8-azabicyclo[3.2.lct-3-yl)-- 5,6,7,8-tetrahydro-l-naphthalenecarboxamide; or N-(endo-l-azabicyclo[3.3.llnon-4-yl)-5,6,7,8-tet ahydrol-naphthalenecarboxamide; 26890-7F I I one obtains the following compounds: 2-(l-azabicyclo[2.2.2]oct-4-yl))-l,2,4,5,6,7-hexahydrocyclohept[de]isoquinolin-l-one; 2-(endo-9-methyl-9-azabicyclo[3.3.]non-3-yl)l,2,4,5,6,7-hexahydrocycloheptdelisoquinolin-l-one; 2-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)l,2,4,5,6,7-hexahydrocyclohept[delisoquinolin-l-one; 2-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)- 1,2,4,5,6,7-hexahydrocycloheptcdeisoquinolin-l-one; or 2-(endo-1-azabicyclo[3.3.lnon-3-yl)- 1,2,4,5,6,7-hexahydrocyclohept[de] isoquinolin-l-one EXAMPLE 7 PREPARATION OF COMPOUNDS OF FORMULA I WHERE n IS 1, 2 OR 3 AND THE DASHED LINE REPRESENTS 2 HYDROGEN ATOMS.

2,3,A. (S)-2-(l-AzABXCYCLO[2.2.2JOCT-3-YL)- 2, 3a,4,5, 6-HEXAHYDRO.-lH-BENZ de] ISOQUINOLIN-1-ONE (A compound of Formula IB wherein n 2, p q 0 and R 3 1-azabicyclo[2.2.2oct-3-yl; Reaction Scheme I, Step 3) 4044 The reduction of 0.32g (1.1 mmol) of the free base 4'4c mpg a of (S)-2-(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5, 6tetrahydrobenzde]isoquinolin-1-one (Compound C of o*v* 1 Example 5A) in acetic acid (5 ml) and 3 drops of a perchioric acid with 20% palladium hydroxide on carbon (0.1 g) was carried out at 850C and 50 psi for 24 hours.

The catalyst was removed by filtration and the filtrate S. was concentrated under reduced pressure. The residue was dissolved in water (10 ml), basified with ammonium hydroxide solution, and extracted with ethyl acetate.

The ethyl acetate was dried with anhydrous potassium carbonate, filtered, and evaporated to afford a 26890-FF -59diastereomeric mixture of (S)-2--(l-azabicyclo[2.2.2]oct- 3-yl)-2,3,,3a,4,5,6-hexahydro-lH-beriz[delisoquinolin-l-one (0.18 g) as a semisolid. Crystallization from a mixture of ethanolic hydrochloric acid, isopropanol, and ether afforded 0.8 g of the hydrochloride salt [Compound L (HCl)] as white crystals; m.p. >270 0 C. Anal.: Calcd. for Cl 9 Hl 4

N

2 OHClI 0.25 H 2 0: C, 67.64; H, 7.62; N, 8.30%.

Found: C, 67.38; H, 7.70; N. 8.10%.

By substituting other compounds prepared in Examples 4, 5 and 6 for (S)-2-(l-azabicyclo[2.2.2]oct- 3-yl)--2,4,5,6-tetrahydrobenztdelisoquinolin-l-one, other of of compounds of Formula I where n is 1, 2 or 3 and the dashed line represents 2 hydrogen atoms are obtained.

C. A solution of 19.7 g (59.5 mmol) of the hydrochloride salt of (S)-2-(l-azabicycloll2.2.2]oct-3-yl)of acetic acid containing 2 g of 20% Pd(OH) 2 was hydrogenated at 60 psi and 80-85 0 C for 20 hours. The mixture was filtered and evaporated. The residue was partitioned between aqueous ammonia and dichloromethane and the organic layer was dried (Na 2

SO

4 and evaporated.

The crude free base mixture was dissolved in 100 ml of 25 ethanol, acidified with ethariolic hydrochloric acid, and treated with ether to precipitate the HCl salts of (3aS,3'S)-2-.(l-azabicyclo[2.2.2]-oct-3-yl)-2,3,3a,4,5,6hexahydro-lH-benz (del isoquinolin-l-one and the (3aR,3'S)-diastereompr. Two recrystalizations from ethanol afforded the pure HCl salt [Compound-M of the (3aS,3tS)-diastereomer, m.p. 296-297 0 C, [cUD -98 (c

H

2 yield 6 grams). The free base (Comound M) has a m.p. of 87-88*Ct EcUID- 136 0 C (c 0.25 chloroform).

IGHVM

1HVM26890-FF The mother liquors from the above crystallizations were combined and chromatographed on silica gel methanol-dichloromethane, 1% ammonia to give an enriched fraction of the [3aR,3'S]-diastereomer.

from ethyl acetate-hexane gave pure [3aR,3'S3-diastereomer base which was converted to the HC1 salt [Compound N (HC1)1 from ethanolether, m.p.

270-272 0 C; [a]D 73 (c 0.2, D. In an analogous manner, following the hydrogenation procedure of Section C, the HC1 salts of the (3aR,3'R)-diastereomer [Compound O (HC1)1 with a Sm.p.>280 0 C, [a]D 950 (c 0.2 H20) and of the (3aS,3'R)-diastereomer [Compound P (HC1)1 with a m.p.

15 275-276 0 C, [a]D -680 (c 0.3, H20) can be isolated.

E. Using 10% Pd on carbon and Pearlman's So:. catalyst Compound C of Example 5A is hydrogenated in tetrahydrofuran to give Compounds M of HC1 salt 2 295 0 C) and N of HC1 salt 272 0 C) in a ratio of about 3:2. Using 10% Pd on carbon Compound C is hydrogenated as the or camphorsulfonic acid salt in ethyl actetate to Compounds L and M in a ratio of about 1:3.

Using 10% Pd on carbon Compound C is hydrogenated as the acetate in ethyl acetate to Compounds L and M in a ratio of about 0.85:1. Using 10% Pd on carbon with 61.9% water (Degussa) Compound C is hydrogenated as the free base in toluene to Compounds L and M in a ratio of 2.1:1. Using 5% Pd/BaSO 4 Compound C is hydrogenated in ethyl acetate to Compounds L and M in a ratio of 2.7:1.

26890-FF k I -61- EXAMPLE 8 A. (S)-2-(1-AZABICYCLO[2.2.2]OCT-3-YL]- 2,4,5,6-TETRAHYDROBENZ[de]ISOQUINOLIN-1-ONE

HYDROCHLORIDE

(A compound of Formula I as a pharmaceutically acceptable acid addition salt) (S)-2-(l-azabicyclo[2.2.2]oct-3-yl]- 2,4,5,6-tetrahydrobenz[de]isoquinolin-l-one is recrystallized from n-propanol/hydrochloric acid to form the corresponding hydrochloride salt.

B. Other hydrochloride salts of the free base 4 compounds of Examples 1-7 are similarly prepared.

5 EXAMPLE 9 S. A. (S)-2-(1-AZABICYCLO[2.2.2]OCT-3-YL]- 2,4,5,6-TETRAHYDROBENZ[de]ISOQUINOLIN-1-ONE (A compound of Formula I as a free base) (S)-2-(l-azabicyclo[2.2.2]oct-3-yl]- 2,4,5,6-tetrahydrobenz[de]isoquinolin-l-one hydrochloride is treated with a molar excess of ethanolic potassium 25 hydroxide to form the corresponding free base (Compound m.p. 117-118 0

C.

B. Other free base compounds are similarly obtained from the correspondina acid addition salts of the compounds prepared in Example 1-8.

26890--FF -62- EXAMPLE (S)-2-(l-AZABICYCLO[2.2.2]OCT-3-YL)- 2,4,5,6-TETRAHYDRO-1H-BENZ[de]ISOQUINOLIN-l-ON .J.FDE (A compound of Formula I as the N-oxide) m-Chloroperoxybenzoic acid (0.82g, 4.7 mmol) a: added in small portions at 0°C to a solution of (S)-2-(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro- -benz[de]isoquoinolin--one (Example 5A) (1.16 g, 3.9 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for additional 0.5 hour at 0°C. The solvent was removed under reduced pressure and the residue was purified by column chromatography 5 methanol in dichloromethane and 1% ammonium hydroxide) to give the N-oxide of (S)-2-(l-azabicyclo-[2.2.2]oct-3-yl)- 2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-l-one (Compound 0) (0.75 g; 62% yield) as an amorphous solid; m.p. 73-75 0

C.

Other N-oxides of this invention are prepared by substituting other compounds of Examples 4-6 into the above procedure.

EXMPLE 11 25 5-HT 3 RECEPTOR SCREENING ASSAY This example describes an in vitro assay for determining the 5-HT 3 receptor affinity of the compounds of this invention. The method is essentially the method 30 described by Kilpatrick et al., previously cited, which measures the affinity of a compound for the 5-HT 3 receptor of the rat cerebral cortex. Compounds of this invention are screened for affinity at the 5-HT 3 receptor of rat cerebral cortex radiolabelled with 3 H]quipazine.

26890-FF -63- Membranes are prepared from the cerebral cortices of rat brains homogenized in 50 mM Tris buffer (pH 7.4 at 4 0 C) using a Polytron P10 tissue disrupter (setting 2 x 10 sec bursts). The homogenate is centrifuged at 48,000 x g for 12 min and the pellet obtained is washed, by resuspension and centrifugation, three times in homogenizing buffer. The tissue pellets are resuspended in the assay buffer, and are stored under liquid nitrogen until required.

The binding assays are conducted using a Tris-Krebs assay buffer of the following composition (mM): NaC1, 154; KC1, 5.4; KH2PO 4 1.2; CaC1 2 .2H 2 0, 2.5; MgC1 2 1.0; glucose, 11; Tris, 10. Assays are conducted at 25 0

C

at 7.4 in a final volume of 0.25. Zacopride (1.0 pM) is 5 used to define the non-specific binding (NSB). 5HT 3 receptors present in rat cortical membranes are labelled using 0.3-0.7 nM 3 H]quipazine (specific activity 50-66 i *Ci/mmol; New England Nuclear) in the presence of 0.1 pM paroxetine to prevent 3 H]quipazine binding to 2 uptake sites. The rat cortex membranes are incubated with 3 H]quipazine in the presence of 10 different concentrations of compound to be tested at concentrations ranging from 1x10 12 to 1x10 4 molar. Incubations are conducted for 45 min at 25 0 C and are terminated by vacuum filtration over Whatman GF/B glass fiber filters using a Brandel 48 well cell harvester. After filtration the S* filters are washed for 8 sec with 0.1 M NaC1. The filters are pretreated with 0.3% polyethyleneimine 18 hr prior to use in order to reduce filter binding of the S* 30 radioligand. Radioactivity retained on the filters is determined by liquid scintillation counting.

The concentration of compound producing inhibition of radioligand binding is determined by use of 26890-FF I i -64an iterative curve fitting procedure. Affinities are expressed as the negative logarithm of the IC 50 value

(PIC

5 0 L- Compounds of this invention exhibit PIC 50 values showing 5-HT 3 receptor antagonist affinity, e.g. values greater than 6.

EXAMPLE 12 GASTRIC EMPTYING OF TEST MEAL IN RATS This Example describes an in vivo method of determining the gastrointestinal activity of the compounds of the invention. The method :ks the method described by Droppleman et al., previously cited, which measures gastric emptying of test meal in rats.

15The following formulation is used as the test meal administered to the rats. Twenty g of cellulose gum *~,(Hercules Inc., Wilmington, Delaware) is slowly added to 200 ml of cold distilled water while being mixed in a Waring blender at approximately 20,000 rpm. Mixture of the cellulose gum continues (approximately 5 min) until complete dispersion and hydration of the cellulose gum 'lovehas taken place. Three beef bouillon cubes are dissolved in 100 ml of warm water and then blended into the cellulose solution followed by 1.6 g of purified casein 2r (Sigma Chemical Co., St. Louis, MO), 8 g of powdered C confectioners sugar, 8 g of cornstarch, and 1 g of C powdered charcoal. Each ingredient is added slowly and mix~ed thoroughly resulting in approximately 325 ml of a C. dark gray to black, homogenous paste, The meal was then refrigerated overnight to allow for trapped air to escape. Prior to the assay the meal is removed from the refrigerator to allow it to warm to room temperature.

once to room temperature, 3 ml of meal is filled into ml disposable syringes for oral dosing of animals, with lHVM26890-FF each animal requiring one filled syringe. Five test meal samples are weighed oe an analytical balance and these weights were averaged to find a mean test meal weight that is later used in the calculations of meal emptied.

Mature (170 to 204 g) male Sprague-Dawley rats are deprived of food for 24 hrs with water ad libitum. On the morning of the study each animal is weighed and randomly assigned to treatment groups consisting of ten animals per group. Starting at 0 hr each animal receives 1 either control, test, or reference substance (metoclopramide) by intraperitoneal injection. At time hr each animal is orally dosed with 3 ml of test a meal. At time 1.5 hr each animal is sacrificed by carbon 0* dioxide inhalation. The stomach is removed by opening each animal's abdomen and carefully r'-:.ping and cutting -the esophagus and cutting just below the pyloric S. sphincter of the stomach. Each stomach is placed, taking care not to lose any of the stomach contents, on a small, ""previously weighed and correspondingly labeled 7 ml weigh 2 boat and immediately weighed on an analytical balance.

Following weighing each stomach is cut open along the o lesser curvature of the stomach and was rinsed with tap water and gently blotted dry to remove excess moisturt.

•After roweighing the empty stomach, the difference 25 between the wiT ght of the full stomach and the empty 25 stomach minus the weigh boat weight indicates the amount o of of test meal remaining in the stomach, and this value is subtracted from the average weight of 3 ml of test meal to yield the quantity of test meal emptied during S" 0 the 1.5 hour post injection time period. The mean and standard deviation amount of meal emptied by test and reference groups are compared to the mean and standard deviation of meal emptied by the control group by use of Dunnett's t-test (Statistical Association Journal, 26890-FF k I -66- December 1955, 1096-1121). Per cent difference from control is also calculated for the treatment groups.

The compounds of this invention when administered intraperitoneally increase gastric emptying of a test meal in rats as shown by the following results: Compound Mean 50 (qm.)c Ac control* (25) 1.77 0.20 N(HC1) 6) 2.44 0.18* 22.5 M(HCl) (10) 2.32 0.25 16.3 C(HCl) (10) 2.03 0.36* 27.2 Q 9) 2.27 0.20* 32.7 metocoopramide* (29) 2.42 0.26* 37.3 9 9 oe. 15 Significance from control; PL 0.05.

a Mean results from 3 separate experimental runs.

S*c, Percentage increase from control is calcaluted and statistical analysis is performed using controls particular to each experimental run.

EXAMPLE 13 CISPLATIN-INDUCED EMESIS IN FERRETS «e This study shows the effects of compounds of Formula I, given intravenously on cisplatin-induced emesis in ferrets.

2 5 Adult, Rale, castrated 4errets are allowed food and water ad libitum both prior to and throughout the testing period. Each animal is randomly chosen and anesthetized S* with a metofane/oxygen mixture, weighed and assigned to one of three test groups. While anesthetized an incision is made along the ventral cervical region approximately two to foar centimeters in length. The ju,4lar vein is then isolated and subsequently cannulated with a capped saline filled PE-50 polyethylene tubing. The cannula is 26890-FF.

I 4 -67exteriorized at the base of the skull and the incision closed with wound clips. The animals are then returned to their cages and allowed to recover from anestheria before intravenous (iv) administration of either vehicle ml/kg) or test compound (1.00 mg/kg). Within minutes of the administration of a test compound an iv dose of cisplatin (10 mg/kg) is given. The animals are then observed for five hrs (post dosing) and emetic responses vomiting and/or retching) are recorded.

For purposes of this Example and of Example 16, vomiting is defined as the successful evacuation of stomach contents, while a single episode of retching is defined Sas rapid and successive efforts to vomit (within a one minute time period). At the end of this observation 15 period each animal is euthanised by a lethal barbiturate ;injection.

Emetic responses are represented as time to S* onset of emesis, total vomiting episodes and *o total retching episodes. Means and standard 2 deviations of the test groups are compared to those of the reference groups. Significance is determined by Student's t-test when comparing a single treatment group to the vehicle control or by Dunnett's comparative analysis when more than one treatment group is compared 25 to a single vehicle.

25 Intravenously administered compounds of Formula I are anti-emetic in this assay as shown by the following resultst 26890-FF -68- Treatment Veh icl e N (HC1) Vehicle M (HC 1) Dose, P.O.

(mo/ki) 1.0 mi/kg 0.1 1.0 mi/kg 0.1 1.0 mi/kg 0.1 1.0 mi/kg 0.1 Tirme to N Onset 33. 6±6 .9 79 .7±16. 6 33 6±6. 9 90.0t21. 2 54 0±10. 9 86 5±2. 1 50 0±4 0 76. 6 Vehicle C (NC1) Vehicle M(HCl) Retching Episodes 11.0±t2. 9 3 .5t2 .3 11. 0±2 9 0. 3 11. 4t4. 3 1. 0±1. 5 11. 7t2. 3 3 5t3 7 11 8±4. 6 7 4t3 3 16 5t2. 6 0. 5±1. 2 Vomiting Blpj sodes 14. 2±5. 3 3±2 .7 14. .2±5 0. 8±1.3 13. 2±7. 3 0. 7±1. 0 16. 5±5 8 5. 3±7. 2 12. 5-4 6 8±3 4 19. 5±3 .2 0±0 Vehicle 1. 0 mil/kg V(IHBr) 0.1 Vehicle 1.0 mi/kg M(HCl) 0.1 94 CO 0

S*

99 *000 *004 ~a 0 ae a *690 94 946e 37.2±5. 0

N/A

off# 84409 *000* Proceeding as in this Example, but administering the test compounds by oral route, the anti-emeti6- effects of compounds of Formula I may be evaluated. Orally administered compounds of Formula I are anti-emetic in this assay.

EX AMPLE 14 3 ANTAGONIST ACTIVITY IN RATS (VON BEZOLD-JARISCH REFLEX) This Example describes an in vivo method for determining the 5-NT 3 antagonist activity of the compounds of the invention. The method is a modified version of the methods described by Butler et al., Cohen et al., and Fozard, all previously cited, which measure 5-HT 3 antagonist in rats; where 2-methyl- 3-hydroxytryptamine was used rather than 5-NT itself.

1 HVM26890-FF -69- Male Sprague-Dawley rats, 250-380 g are anesthetized with urethane (1.4 g/kg, ip), and cannulated (trachea, left femoral vein and either duodenum or jugular vein). The heart rate is recorded, using Gould ECG/Biotech amplifiers. After at least 30 min equilibration, each rat is titrated (iv) with tryptamine (2-m-5HT) and a minimal dose that induced a sufficient and consistent bradycardia is chosen.

For an intravenous dose range (potency) study, the rat is challenged with the selected dose of 2-m-5HT every 12 min. A test compound is administered intravenously in increasing doses 5 min before each injection of until the response to 2-m-5HT is blocked. A separate 15 group of rats receiving vehicle is similarly tested.

15 e For duration studies, a single dose of a test compound or vehicle is injected intravenously or intraduodenally to the rat and the rat is challenged with at 5, 15, 30, 60, 120, 180, 240, 300 and, in some 2 studies, 360, 420 and 480 min post dose.

For both potency and duration studies heart rate (beats/min) is recorded continuously foi the duration of the study. The peak decrease in heart rate evoked by is monitored, using a computer. The change in S 25 responses to 2-m-5HT before and after administration of the vehicle or the compound is calculated. This is expressed as percent inhibition from the predose value.

Data are analyzed using a one-way repeated measures ANOVA and followed by pairwise comparison to vehicle control using Fisher's LSD strategy. From a dose-response curve so constructed, an ID 50 value is obtained to represent the dose that inhibited 50% of the bradycardic effect induced by 26890-FF Compounds of this invention are active in this assay. Specifically, Compounds C(HC1), M, M(HC1), N(HC1) and R(HCI) are equal in activity to Odansetron or more active than Odansetron (ID50 3.2 mg/kg).

EXAMPLE THE ANXIOLYTIC BEHAVIOR MODEL This Example describes an in vivo method for 1 determining the CNS activity, i.e. the anxiolytic activity, of compounds of the invention.

Naive male C5BI/6J mice, 18-20 g, are kept in 00 00 groups of 10 mice in quarters controlled for sound, *temperature and humidity. Food and water are available 0* 06.0 ad libitum. The mice are kept on a 12 hr light and 12 hr s dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m. All experiments begin after at least 7 days have lapsed after arrival at the site.

The automated apparatus used for the detection of changes in exploration was obtained from Omni-Tech Electronics Columbus Ohio and was similar to that of o* Crawley and Goodwin (1980), as described in Kilfoil et al., cited previously. Briefly, the chamber consisted of a plexiglass box (44 x 21 x 21 cm), divided into two 25 chambers by a black plexiglass partition. The partition dividing the two chambers contained a 13 x 5 cm opening through which the animal could easily pass. The dark chamber (42 cm x 21 cm x 30 cm) has clear sides and a white floor. A fluorescent tube light (40 watt) placed 3 above the chambers provides the only illumination. The Digiscan Animal Activity Monitor System RXYZCM16 (Omni-Tech Electronics) is used to record the exploratory activity of animals within the test chambers.

Prior to administration of vehicle (DDH 2 0) or 26890-FF r V -71active compound at doses of 1.0 mg 10 mg/kg all animals were given 66 min. to ac; limatize to the laboratory environment. All animals having received intraperitoneal injections of either active or vehicle are returned to their home cages for a 15 min. pretreatment period. From here, each animal is individually (separately) placed in the center of the light area of one of the test apparatuses and monitored for 10 min. Measurements include time spent in each compartment, general locomotor 1 activity, rears and latency (the time for the mouse to move to the dark chamber when first placed in the center of the lighted area): 2 **ae W o e e3 B

I

*o B *o a OO 26890-FF

COMPOUND

Ondansetron E(HC1) C (HCl) M4 (HC1) P (HCI)

SHUTTLE

ACTIVITY

Mean SD 121.0±12.4* 266.5±43.4* 159 .8±22.8 59.8± 8.2 148.4±14.8* 7.5 95. 8 40.2 31.9 92.7

LOCOMOTOR

ACTIVITY

(LIGHT AREA) Mean SD A 1528± 77.8* 52.6 1677± 66.9* 34.6 1534t 72.9* 41.1 1844± 54.4* 57.6 1696±112* 33.4 TIME DARK AREA (SEC) Mean ±t SD A 499.4±14.33* -12.8 504.8±13.2* 94 452.4±17.9* -20.1 454.5±17.4* -18.2 479.0±12.5* -12.5 LATENCY (SEC) Mean ±t SD A% 6.7±1.5 4.7 2.6±0.2 4.0 7.6±0.9 80.9 8.1±1.2 86.9 7.6±1.1 65.2

ACTIVITY

DARK AREA 2* Mean SD A 78.8±t2.4* -13.1 78.1±2.3 77.4±2.7* -12.3 71.3±2.8 -18.1 74.4t1.9 -14.6 Significance from con~trol; p <0.05 Percentage change frot control is calculated and statistical analysis is perlformed using controls particular to each experimental run.

2* Unaltered or decreased locomnotor activity in the dark area is an indication that increased exploratory activity is not the result of an overall increase in locomotor activity but is the reflection of anxiolytic activity.

S SOS S S S S 5 5 55 S S S 55 5 5 55 55 S S S 5 5 SO S .0 55 *0 505 550 5 OS.

S S S 0 0 S 550 5 5 0 0 S. S S S 5 0 0 O 9 0 5 55 54 0 0 5 5 0 5 055 5

I

-73- The two compartment exploratory model of Crawley and Goodwin demonstrates that anxiolytic (antianxiety) compounds of Formula I increase the amount of time spent in the light area, increase the amount of shuttle activity in the light area and either do not affect or increase locomotor activity in the light area.

The above results demonstrate that the compounds of this invention are effective in this assay.

EXAMPLE 16 CISPLATIN-INDUCED EMESIS IN DOGS The following describes the procedure for determining the intravenous effects of compounds of Formula I on cisplatin-induced emesis in dogs.

S. Male and female dogs (6-15 kg) are fed one cup of dry dog food. One hour following feeding, cisplatin (cis-diamminedichloroplatinum) is administered i.v. at 3 mg/kg. Sixty minutes after the administration of 2 cisplatin, either vehicle or test compound is injected i.v. at 0.1 ml/kg and 1.0 mg/kg, respectively. The dogs are then observed continuously for a 5 hour period and the emetic responses vomiting and/or retching) are recorded.

25 Emetic responses are represented as time to onset of emesis, total vomiting episodes and (3) total retching episodes. Means and standard deviations of the test groups are compared to those of the reference groups. Significance is determined by Student's t-test when comparing a single treatment group to the vehicle control or by Dunnett's comparative analysis when more than one treatment group is compared to a single vehicle.

26P90-FF -74- Compounds of Formula I exhibit anti-emetic activity in this assay.

EXAMPLE 17 The Mouse Light/Dark Withdrawal Anxiety Test The following procedure describes a method to determine whether compounds of Formula I affect the anxiety that occurs after abruptly ceasing chronic 1 treatment with drugs of abuse.

Naive male BKW mice (25-30 g) are caged in groups of ten in quarters controlled for sound, temperature and humidity. Food and water are available ad libitum. The mice are kept on a 12 hour light cycle and 12 hour dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m.

15 All experiments begin at least 7 days after arrival on site.

Anxiolysis is determined by the two-compartment exploratory model of Crawley and Goodwin (see Example 15). Measurements include time spent in the light Scompartment, locomotion activity (grid crossings/5 min.), rears and latency (the time for the mouse to move to the dar^t chamber when first placed in the center of the lighted area).

25 Increased exploratory activity in the lighted area Sis induced by treating the mice for 14 days with alcohol w/v in drinking water), nicotine (0.1 mg/kg, i.p., twice daily) or cocaine (1.0 mg/kg, twice daily).

Anxiolysis is assessed 1, 3, 7 and 14 days after commencement of the drug regime. The treatment is abruptly ceased and exploratory activity in the lighted area is determined 8, 24 and 48 hours thereafter.

Vehicle or test compounds zre administered during the withdrawal phase by intraperitoneal injection. Activity 26890-FF is measured as inhibition of the decrease in anxiolytic behavior after the alcohol, cocaine or nicotine treatment is ceased.

Compounds of Formula I decrease the anxiety with drug withdrawal in this model the following results: Time in Latency Rears/5 Min Dark W% in.Liciht Control diaz W/D W/Di-C(HC1)* mc mm C I S S 'mm.

.me.

C B B. S me me m mm..

mm SB S mom.

58.3t5.9 8.0±0.7 70.0±8.0* 1.8±0.1* 29.4±3.2** 27.8±2.9** 59.0±6.0 9.6±1.5 69.7±7.0* 2.0±0.01* 29.0±3.0** i9.7±3.5** Control nic W/D W/D+C(HCl)0 Control alc W/D W/D+-C(HCl) 0 Contrl coc W/D W/D+C(HCl)o 22.4t 2.4 8.4t 0.9* 97.8±10.7** 26.0± 2.8 9.6± 1.1* 90. 1t10.*4 28.6t 3.2 12.3t 1.8* 73 5±7 .6 30.2t 3.3 as shown by Crossings/ 5 Min in Lictht 24 2 .7 7.8t' 09* 113 .2±13.1* 33 3 .6 10 1. 4 100. 0±11. 0* 3 7 4. 0 14.3± 1.7* 88.0± 58 .4t6 0 80.0±8.2* 63 .7t6 .6* 7 .3±0.9 2 3* 9.6±1.4* 58.0±5.9 9.8±1l.5 74.5t75* 1.8±0.2* 25.8±t2.7** 20.0±2.9** 34.2t 3.6 8.6± 1.0* 8.0± 0.9* 9l.0t10.2** 117-0±13.0** W/D =withdrawal diaz =diazepam; nic -nicotine; aic =alcohol; coc. cocaine *significance from control; p <0.01 *significance from W/D; p <0.01 o 1 pi/g/kg of C(HCl) is administered i.p. mccc..

B

mmmc.

S m cm em mom mm S m m mm EXAMPLE-18 THE MOUSE HABITUATION/COGNITIVE ENHANCEMENT TEST The following describes a model to determine the enhancing effects of compounds of Formula 1.

Young adult and aged BIKW mice are caged in groups of ten in quarters controlled for sound, temperature and IOHVM 1HVM26890-FF -76humidity. Food and water are available ad libitum. The mice are kept on a 12 hour light cycle and 12 hour dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m.

All experiments begin at least 7 days after arrival on site.

Anxiolysis is determined by the two-compartment exploratory model of Crawley and Goodwin (see Example 15). Measurements include time spent in the dark area, locomotion activity (grid crossings/5 min.), rears and latency (the time for the mouse to move to the dark chamber when first placed in the center of the lighted area).

Mice are exposed to the two-compartment test area over a 4 day period. The young mice habituate to the 5 test area by day 3 and spend less time exploring the lighted area, whereas exploratory activity remains constant for the aged mice through day 4. Vehicle or test compounds are administered to the aged mice by intraperitoneal injection. Activity is measured as a 2 decrease in exploratory activity on days 2, 3, and 4.

Compounds of Formula I enhance cognition in this model as shown by the following results for Compound C(HCl): Day 3 25 Time Dark Latency Locomotor 1 2 3 4 Area Rears 3 Activity 4 o young (control) 83.7±7.8 2.7±0.6 14.6±1.4 26.2t1.9 aged (control) 32.6±3.1 18.0±2.3 49.2±4.6 58.1±5.7 aged treated 75.2±6.2 4.7±0.6 13.8±1.5 21.0±1.9 1 Percentage of time over a minute period spent in the dark chamber.

2 The time for the mouse to move to the dark chamber when first placed in the center of the lighted chamber.

3 Number of rears/5 min. in the lighted chamber.

4 Number of grid crossings/5 min. in the lighted chamber.

26890-FF -77- EXAMPLE 19 Intravenous 1-Month Toxicity Study in Rat A. The following describes tLe procedure for determining the effects of chronic intravenous administration of compounds of Formula I in the rat.

Male and female rats are administered i.v. bolus injections of a comipound of Formula I at 0.1, 1.0 and 10.0 mg/kg once daily for 1 month. A separate group of rats are treated similarly with vehicle to serve as experimental controls.

During the course of treatment body weight, food intake and clinical observations are recorded weekly.

Ophthalmalogic examinations and urinalysis are conducted during the last week of treatment.

15 After 1 month of treatment all rats are necropsied and clinical chemistry and hematology evaluations of blood samples are performed.

B. The procedure described in Part A was carried 2 out for Compound C(HC1) of Example 5A with the following results: Clinical Observations All rats were clinically normal at all S* observations.

25 Mortality There were no unscheduled deaths during the study.

The group average body weights of male rats given 0.1 mg/kg/day of Compound C(HC1) were comparable to vehicle-treated males. Male rats given 1 to 10 mg/kg/day of the compound gained 26890-FF -78slightly less weight to than control males. In contrast, femaleL in all groups treated with Compound C(HC1) gained 17% to 23% more weight than control females. Differences in weight gain of either sex, when present, were not dose dependent.

Food Intake Food intake was comparable among all groups.

Ophthalmologic Examinations No treatment-related ophthalmologic changes were present.

S**

Clinical Pathology 15 There were no treatment-related differences 0469 .in hematology or clinical chemistry results in animals given 0.1 or 1 mg/kg/day of Compound C(HC1) or in males given 10 mg/kg/day. Female rats given 10 mg/kg/day had slightly lower erythrocyte counts and hemoglobin and hematocrit measurements than controls. Additionally, females in this group had slightly higher sodium levels than controls. No treatment-related changes in urinalysis data were 25 present.

25 Patholocgy No gross or microscopic pathologic hanges of drug-related toxicity were present in male or female rats given 0.1, 1, or 10 mg/kg/day of Compound C(HC1). Liver weights and liver-weight-to-body-weight ratios were higher in females given 10 mg/kg/day than in vehicle-control females.

26890-FF -79- C. No undue manifestations of chronic toxicity were observed with other compounds of Formula I.

EXAMPLE ACID ADDITION SALTS To a solution of Compound C of Example 5A (about 0.3 kg) in i-propanol is added a solution of HC1 gas dissolved in i-propanol keeping the temperature below 25 0 C until no more solid precipitates. The solid is isolated and washed with i-propanol. The solid is dissolved in i-propanol with the aid of deionized water which is subsequently removed by azeotropic distillation. The solution is cooled and aged for at least 2hrs. The product is isolated, washed with S. S. i-propanol and dried at 50-75°C under reduced pressure.

G"e The product may be upgraded by recrystallization from i-propanol using deionized water to aid in dissolution.

The mother liquor may be reworked by concentration and 2 recrystallization from i-propanol with the aid of deionized water for dissolution. The yield of Compound C(HC1) is 60-95%, and the m.p. conforms to that given in Example 25 EXAMPLE 21 PREPARATION OF COMPOUNDS OF FORMULA I WHERE N IS 2, THE DASHED LINE REPRESENTS A BOND AND R 1 IS A SUBSTITUENT OTHER THAN HYDROGEN 0 A. A solution of 830 mg of (1-azabicyclo[2.2.2]oct-3-yl)-2-methoxy-5,6,7,8tetrahydro-l-naphthalene carboxamide (2.6 mmol) in 75 ml tetrahydro-uran is cooled to -50 0 and 6.6 mmol of n-butyl lithium in hexane are added. After the addition 26890-FF is complete the reaction mixture is allowed to warm up to 0 C for about 30 minutes while a deep red solution is obtained. The solution is cooled to -40 0 C and 0.5 ml dimethyl formamide added in one portion, and then allowed to warm to room temperature, and quenched with aqueous hydrochloric acid. The layers are separated and the aqueous layer made basic with ION aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate was dried with brine and anhydrous magnesium sulfate and evaporated. After flash chromatography with 5% methanol in dichloromethane and 1% ammonia 80 mg of (S)-2-(l-azabicyclo[2.2.2]oct-3-yl)- S* 9-methoxy-2,4,5,6-tetrahydro-lH-benz[de]isoquinolin-1-one (Compound T) is obtained which is converted to the o hydrochloride salt [Compound T (HC1) m.p. 270-271 0

C,

15 [a25D -21.1 0 (C 0.27, H 2 C, 65.74; H, 7.03; N, 7.67.

Found: C 65.48; H, 7.04; N, 7.56] in ethanol hydrochloric acid/ether.

B. By following the procedure of Part A of this 2O example with 1.81 grams of the 4-methoxy carboxamide of Part C of Example 2, 1.6 grams of (S)-2-(l-azabicyclo [2.2.2]oct-3-y3)-7-methoxy-2,4,5,6-tetrahydro-lH-benz[de] isoquinolin-1-one are obtained as the hydrochloride salt S 25 'Compound X (HCl); mop. 296/7 0 C (decomposition)].

q SC. By following a procedure similar to that of Part A of this example with 1.02 mmol of

S

S. I. azabicyclo[2.2.2]oct-3-yl)-4-benzyloxy-5,6,7,8-tetrahydro- 1-naphthalene-carboxamide and 2.6 mmol of n-butyl-lithium and initial cooling to -70 0 C and cooling to -600C before addition of dimethylformamide 110 mg of the 7-benzyloxy analog are obtained as the hydrochloride salt (Compound S (HC1); m.p. 244/5 0

C.

26890-FF -81- D. A solution of 100 mg (.31 mmol) of Compound X (HC1) of Part B of this example in 5 ml of 48% HBr is heated to 80-90 0 C for 16 hours and the completion of the reaction monitored with TLC. The reaction mixture is concentrated under reduced pressure, 5 ml dioxan are added and the mixture concentrated again. The residue obtained is dissolved in 3 ml of hot i-propanol, the solution is filtered while hot, concentrated to 1.5 ml and stored at room temperature. 40 mg of brown crystals of (S)-2-(l-azabicyclo[2.2.2]oct-3-yl)-7-hydroxy-2,4,5,6tetrahydro-lH-benz[de]isoquinolin-l-one hydrochloride are obtained as brown crystals and dried in vacuo (Compound V (HBr) m.p. 319-21 0

C).

E. Using 500 mg of Compound X (HC1) and the procedure of Part D of this example 180 mg of Compound V (HBr) are obtained: [a]25 41 0 (c 0.02 H 2 0) F. A mixture of 50 mg of Compound S (HC1) of 2 Part C of this example and 15 mg of 10% Pd on carbon in 7 ml ethanol are stirred under hydrogen for 15 hours at room temperature. The progress of the reaction is o monitored by TLC and shows conversion to Compound V which conformed to the compound obtained in Part D of this 25 example. The catalyst is removed by filtration and the filtrate concentrated under reduced pressure. 17.4 mg of Compound V (HC1) are obtained after recrystallization from ethanol.

26890-FF -82- EXAMPLE 22 TABLET FORMULATION by wt. of Compound C 69% by wt. of Lactose, spray dried, NF by wt. of Microcrystalline Cellulose, NF 1% by wt. of Magnesium Stearate '..040 0 t a4 4 Sto 5035 26890-FF.

Claims (7)

1. A compound of Formula I 0 C R 2 )q in which 0 Poe*the dashed line denotes an optional double bond; *6 n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2; each Rl is ii~aependently selected from halogen, 0 l hydroxy, lower alkoxy (optionally substituted with fee0* phenyl), lower alkyl, nitro, amino, amino-carbonyl, (lower alkyl)amino, di(lower alkyl)aminc, and (lower alkanoyl)amino; *004 each R~ 2 is lower alkyl; and "06:0R 3 is selected from at 6a, 3 1 HVM26890-FF C(CH 2 .NR 4 (a) CH) 2 )y (b) Cc) N- R 1 (CH 2 (d) in which x, y, and z are all independently an integer from 1 20 to 3; and R 4 and R 5 are independently Cl 1 7 alkyl, C 3 8 cycloalkyl, *goo C3_ 8 cycloalkyl-C.. 2 alkyl, or a group (CH 2 )tR 6 where t is 1 or 2 and R 6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from CI 1 6 alkyl, C 1 6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C 1 4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, 0 esterified carboxy, and 4 alkyl (optionally S 30 substituted by hydroxy, C 1 4 alkoxy, carboxy,(oesterified carboxy)r inv; hdoyeb~~ ylery); or a pharmaceutically acceptable salt thereof or an N-oxide .:thereof; or an individual isomer or mixture of isomers thereof. 1 HVM26890-FF

2. The compound of Claim 1 wherein p is 0, 1 or 2; n is 1 or 2; q is 0; Rl is halogen, lower alkoxy or amino; and if R 3 comprises Rand R 5 they are each lower alkyl.

3. The compound of Claim 2 wherein n is 1.

4. The compound of Claim 3 wherein p is 0, the dashed line represents a double bond and if R 3 comprises R 4 and R 5 they are each methyl.

155. The compound of Claim 2 or 4 wherein R 3 is b ccl .,21c 1 1-azabicyclo[2,.2.2]oct-3-yl; endo-9-methyl-9-azabicyclo[3 1]non-3-yl; endo-8-methyl-8-eazabicyclo[3 lloct-3-yl; exo-8-methyl-8--azabicyclo[3.2.l7joct-3-yl; or [3.3 .1]non-4-yl. 6. The compzund of Claim 5 wherein R 3 is l-azabicyclo[2.2.2]oct-3-yl, namely 2-(1-azabicyclo[2.2.2Ioct-3-.yl)-l,2,4,5-tetrahydro- cyclopentide] isoquinolin-l-one. 7. The compound of Claim 6 which is 2-il- 0 azabicyclo[2.2.2]oct-3-yl)-1,2,4,5-tetrahydro- 09*o 30. cyclopenta[delisoquinolin-1-one hydrochloride. lHVM26890-FF 8. The compound of Claim 6 which is (S)-2-(l--azabicyclo[12 .2.2]oct-3-yl)-1, 2, cyclopenta[de] isoquinolin-l-one hydrochloride. 59. The compound of Claim 5 wherein R 3 is 8-methyl-8-azabicyclo [3 oct-3-yl, namely, 2- 8-rethyl-8--azabicyclo -oct-3-yl) 1,2,4, 5-cetrahydro-cyclopent [de] isoquinolin-l-one. 10. The compound of Claim 9 wherein R 3 is o8mty--zbcco[..lc--l aey 2-endo-8-methyl-8-azabicyclo[3.2.-oct-3-yl amly l,2,4,5-tetrahydro-cyclopent~de]isoquinolin-l-one. 11. The compound of Claim 2 wherein n is 2. The compound of Claim 11 wherein p is 0, the 0e dashed line represents a double bond and if R 3 comprises R 4 and R 5 they are each methyl. 13. The compound of Claim 12 wherein R 3 is 1l-azabicyclo[2 .2 .2]oct-3-yl; l-azabicyclol2 .2 .2]oct-4-yl; endo-9-methyl-9-azabicyclo[3 llnon-3-yl; erdo-8-methyl.-8-aabicyclo[3.2.1]oct-3-yl; exo-8-methyl-8-azabicylo[3.2.lloct-3-yl; or endo-l-azabicyclo non-.4-yl. a 14. The compound of Claim 13 wherein 00 n 3 is 0 30 l-aza-bicyclo[2.2.2]oct-4-yl, namely 2-(1-azabicyclo[2.2.2]oct-4-yl)-2,4,5,6-tetrahydro- 1H l-benz [de] isoquinolin-1-one. I OHVM 2HVM26890-FF The compound of Claim 13 wherein R 3 is exyo-8-methyl-8-azabicyclo[3.2.ljoct-3-yl, namely 2-(exo-8-methyl-8-azabicyclo[3 .2.111oct-3-yl)- 2,4,5, 6-tetrahydro-lH-benz [de] isoquinolin-l-one. 16. The compound of Claim 13 wherein R 3 is endo -8-methyl-8-azabicyclo[3.2.lloct-3-yl, namely 2-(endo-8--methyl-8-azabicyclo[3 .2 .l]oct-3--yl)- 2,4,5, 6-tetrahydro-lH-benz [de] isoguinolin-l-one. 17. The compound of Claim 13 wherein R3 is l-azabicyclol2.2.2]oct-3-yl, namely 2 -(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6.tetrahydro. 1H-benz ide] isoquinolin-l-one. 18. The compound of Claim 17 which is 2 -(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro- *hIR-benz [de] isoquinolin-1--one hydrochloride.

2021. The compound of Claim 17 which is (S)-2-(l-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6tetrahydro. 1H-ben.z[delisoquinolin-l-one a h re ae The compound of Claim 17 wherich is i 2H-be5,6-tetrhdollbn~eisoquinolin-l-one. 10 -IVM2689 0-FF 22. The compound of Claim 13 wherein R 3 is endo-l-azabicyclo[3.3.llnon-4-yl,namely 2 -(endo-l-azabicyclo[3.3.lnon-4-yl)-2,3,5,6-tetrahydro- 1H-benz[de]isoguinolin-l-one 23. The compound of Claim 2 wherein p is 0, the dashed line represents two hydrogens, and if R 3 comprises R 4 and R 5 they are each methyl. 24. The compound of Claim 23 wherein R 3 is 1-azabicyclo[2.2.2]oct-3-yl; l-azabicyclo[2 .2 .2oct-4-yl; endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl; endo-8-methyl-8-azabicyclo[3.2.lioct-3-yl; exo-8-methyl-8-azabicyclo[3.2.1Joct-3-yl; or endo-l-azabicyclo13.3.1]non-4-yl. r _25. The compound of Claim 24 wherein n is 1. 26. The compound of Claim 24 wherein n is 2. 0 S 20 C 27. The compound of Claim 26 wherein R 3 is 1-azabicyclo[2.2.2]oct-3-yl, namely 2-(l-azabicyclo-[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro- 1H-benz[del isoquinolin-1-one, in particular the (3aS,3'S) iscnier thereof and its hydrochloride salt. 28. The compound of Claim 1 wherein n is 3; C p is 0, 1 or 2; q is 0; R 1 is halogen, lower alkoxy or amino; 9* and if R 3 comprises R 4 and R 5 they are each lower alkyl. 6

26890-FF 89 29. The compound of Claim 28 wherein p is 0, th~e dashed line represents a double bond, and if R3 comprises Rl4 and R5, they are each methyl. The compound of Claim 29 wherein R3 is 1 -azabicyclo[2.2.2]oct-3-yl; 1 -azabicyclo[2.2.2]oct-4-yi; endo -9-miethyl-9-azabicyclo[3.3. 1]non-3-yI; endo -8-methyl-8-azabicyclo[3.2.1]oct-3-yl; exo -8 ,methyl!-8-azabicvyclo[3,2. 1 oct-3-yl; or endo -1-azabicyclo[3.3.1]non-4-y. 31. The compound of Claim 30 wherein R3 is 1-azabicyclo(2.2.2]oct-3- yl, namely (RS -azabicyco(2.2.2]oct-3-yl)-1 ,2,4,5,6,7-hexahydrocyclohept (de ]Isoquinolin-1 -one. 32. The N -oxide of the compounds of Claim 1. 33. The compound of Claim 32 wherein pis0, 1 or 2; q is 0; RI is halogen, lower alkoxy or amino; and if R3 comprises R4 and R5, they are each lower alkyl. 34. The compound of Claim 33 wherein p is 0, and if R3 comprises R4 and R5, they are each methyl. 35. The compound of Claim 34 wherein n Is 2 and R3 is 1 -azabicydo[2.2.2]oct- 6160.6003-yl. 44 36. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of Claims 1 to 31 or 32 to 35 in combination vith a pharmaceutically acceptable excipient. 37. A method for treating a condition chosen from emesis, a gastro- intestin\l disorder, CNS disorder, a cardiovascular disorder and pain in an animal fn need of such treatment, which method comprises administering a therapeutically effective amount of a compound of any one of Claims 1 to 31 or 32 to 35 or a composition of Claim 36to such animal. 38. The method of Claim 37 wherein the condition is a gastrointestinal disorder. 39. The method of Claim 37 wherein the condition is a CNS disorder. The method of Claim 37 wherein the condition is a cardiovascular disorder. 41. The method of Claim 37 wherein the condition is pain. i: 42. A method of treating emesis in a human undergoing cancer treatment using a cytotoxic pharmaceutical agent or radiation at levels sufficient to induce emesis, which method comprises administering an anti-emetic amount of compound of any one of Claims 1 to 31, 32 to 35 or a composition of Claim 36 to such human. 43. A method for treating an animal having a condition in which the HTs receptor plays a role, which method comprises administering a therapeutically effective amount of a compound of any one of Claims 1 to 35 or a composition of Claim 36 to such animal. 44. A process for the preparation f a compound of Formula I 44. A process for the preparation of a compound of Formula I 91 0 (R 1 PV~(C H 2 n in which n is 1, 2 or 3; p isO0, 1, 2 or 3; q is0, 1 or 2; each R1 is independently selected from halogen, hydroxy, lower alkoxy (optionally substituted with phenyl), lower alkyl, nitro, amino, amino carbonyl, (lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; each R2 Is lower alkyl; and R3 Is selected from 0 H 2 x N R 4 a S S U(CH 2 )y (b) N N .R (C2* (d) In whic ux n zaealIdeednl.n.nee rm o3 n c .8 cylolkyl R 4 and Rs are independently aiKylI C3.8 cycloalkyl-C 1 2 alkyl, or a group (CH 2 )tR 6 where t is 1 or 2 and R 6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from C1-6 alkyl, Ci-6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C1-4 alkoxy, trifluoro- methyl, halogen, nitro, carboxy, esterified carboxy, and C 1 4 alkyl or (optionally substituted by hydroxy, C1-4 alkoxy, carboxyi esterified carboxy)ef--- hydrolyzabl.o aoyloxy or a pharmaceutically accept- able salt thereof or an N -oxide thereof, or an individual isomer or mixture of isomers thereof, which process comprises one or more of the following steps: reactively contacting a compound of Formula Ii 0 R 3 NH (R 1 -(CH 2 )n (R 2 )q in which n, p, q, R1, R2, and R 3 are as defined above with a formulating agent in the presence of a strong base to form a compound of Formula I wherein the dashed line is a double bond, reducing the double bond represented by the dashed line in Formula I by hydrogenation to form a compound of Formula I wherein the dashed line represents 2 hydrogens, converting a sait of a compound of Formula I to the corresponding free compound, condensing a compound of the formula R3L, wherein R3 has the above meanings and L is a leaving group with a compound of the Formula XIII, 0 NH (R')p (CH 2 )n (R?)q wherein RI, R2, n, p, q, and the dashed line have the above meanings, converting a compound of Formula I to the corresponding pharmaceutically acceptable salt, (ft oxidizing a compound of Formula I to form the correspond- ing N -oxide of the R3 componern of Formula I, or reducing an N -oxide of the R3 component to the corresponding amine, reducing a R 1 nitro substituent to a Ri amino substituent or alkylating or acylating a Ri amino substituent or alkylating a R1 hydroxy substituent or dealkylating a RI alkoxy substituent or debenzyiating a R1 benzyloxy substituent to the corresponding compound of Formula I, hydrogenating in positions 3a, 4, 5 and 6 a compound of ti Formula XIV 0 (R)p- 4. XIV h.ere (R2)q wherein R1, R2, R3, p and q have the above meanings, separating a mixture of isomers or diastereomers of a compound of Formula I into a single isomur or a diastereomer, or conducting any of steps through with optically active reactants. 94 A process according to Cla..n 44 wherein R3 is selected from the group consisting of 1 -azabicyclo[2.2.2]oct-3-yl; 1 -azabicyclo[2.2.2]oct-4-yl; endo -9-methyl-9-azabicyclo[3.3.l1 non-3-yl; exo -8-methyl-8-azabicyclo[3.2. 1]oct-3-yl; or endo -1-azabicycloE3.3.1]non-4-yi. 46. A compound represented by the formula 0 NH (c H 2 )n (R 2 )1 wherein n is 1, 2 or3; p is0, 1, 2or 3; q isO, 1 or 2' each RI is independently selected from halogen, hydroxy, lower alkoxy (optionally substituted with phenyl). lower alkyl, nitro, amino, amino carbonyl, ::(lower alkyl)amino, di(lower alkyl)amino, and (lower alkanoyl)amino; each R2 is lower alkyl; and R3 is selected from C(CH 2 )x NR 4 (a) N (CHOY (b (c) N -(0H2)u (CH) 2 )z (d) in which u, x, y and z are all independently an integer from 1 to 3; and R4 and R5 are ind'ependently C1.7 alkyl, C3.8 cycloalkyl, C3.8 cycloalkyl-C 1 2 alkyl, or a group (CH 2 )tR 6 where t is 1 or 2 and R 6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from C1.6 alkyl, C1..6 alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two r.substituents selected from 01.4 alkoxy, trifluoromeihyl, halogen, nitro, carboxy, esterified csrboxy, and C 1 4 alkyl (optionally substituted by hydroxy, 01.4 alkoxy, carboxyo,,esterif led carboxy)ep.'y ora individual isomer or mixture of isomers thereof, or salt thereof. 47. The use of a compound according to any of the Claims 1 to for the preparation of a pharmaceutical composition. 48. A compound as claimed in Claim 27 in the form of the (3aS,3's) isomer. 49. A composition as claimed in claim 3A in which the compound is the compound of Claim 48. A method as claimed in any one of claims 37 to 43 in which the compound is the compound of Claim 48. DATED this 25th day of February, 1993. SYNTEX INC. WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA IAS:BB AU66963.WPC DOC S S S